Masamune Shirow's manga series Appleseed is generally considered his life's work. Currently spanning four volumes, it is much longer than any of his other works, which generally are one, or at most two, volumes when put into collected form. The first volume was published (as a collection) in 1985, with the second volume following later that year, and the third and fourth coming in 1987 and 1989. Appleseed book 5 has been "forthcoming" ever since; at this point it's become almost a joke among his fans. Shirow is legendary for how long it takes him to produce new work, but 16 years is really pushing it, even for him. Appleseed, like all of Shirow's work, is published by Dark Horse in the United States.
Appleseed's main characters are the attractive badass Deunan Knute, and her cyborg lover/partner Briareos. At the start of the manga, they are ekeing out a living in the destruction after World War III. The reasons for the war are unknown, but it left behind a number of nasty presents, ranging from radiation to sarin residue, in the destroyed cities. Looters and former military units roam around, and Deunan and Briareos are obviously equipped and trained well enough to handle themselves in this environment. Briareos was a large guy before he went cyborg, and now most of his external body is metal, with what looks like 5 large red lights on his face (which he presumably sees through somehow), and what look remarkably like metal bunny ears on his head. His strength, speed, and advanced sensors give them a substantial advantage over opponents. The metal body leaves some confusion as to how (or if) he and Deunan have, ahem, 'relations', but they are obviously a couple, even if their relationship is non-physical. Deunan is smaller (she sometimes rides on Briareos' shoulder), and has less in the way of brute strength, but is highly skilled in both armed and unarmed combat and is a brilliant tactician. In a training session with a SWAT team, she 'kills' a squad of armed SWAT members starting out only with a knife within the space of 10 minutes.
The story begins shortly before Deunan and Briareos realize that they are being tracked by a highly advanced enemy, who has access to high-quality satellite surveillance systems, armored combat suits, and at least one mini-tank armed with a rather powerful minigun. They are forced/induced to go with a girl who calls herself Hitomi to Olympus, a vast city of peace and civilization which has arisen from the chaos of the war. Olympus is attempting to be a utopian society which will eventually take over the entire world through economic, social, and if need be, military, influence, and ensure that no future wars will ever threaten the future of humanity, as the last war had. Part of their utopian society is based on bioroids, biological androids who appear human, but have certain limitations and abilities which make them distinct from humans, such as limited emotions and higher average intelligence. The intent is that the bioroids will both assist and stabilize human society. A large part of Olympus is run by the supercomputer Gaia, including nearly all public functions, ranging from power control to automated defense systems. Gaia is also used to help decide between courses of action, as it has access to a vast amount of information, and is usually capable of using it to help its masters make the correct decision. However, Gaia starts acting quite irregularly, almost as if it has a plan of its own which it wishes to carry out...
Nearly immediately after arrival, Deunan and Briareos are thrown into a vast political power game related to the human versus bioroid struggle, the fight as to who will control Olympus, and, eventually, the fate of Olympus itself. While everyone claims Olympus is a utopia, there seem to be a number of people intent on committing terrorist acts within the city, which seems a bit odd. Eventually it becomes obvious that Olympus is really a golden cage, beautiful and safe but so constricting that many humans grow frustrated and violent about their place in life.
Shirow's work tends to be both dense and confusing at points, and Appleseed is no exception. Exacerbating the problem, Shirow has four full volumes to build up extremely complex plot points and lines of philosophical reasoning, which at points become nearly incomprehensible. For example, at one point an actual, physical apple seed is used to save the city by firing it into Gaia's core. Presumably Shirow intended that this have some deeper meaning, but hell if I know what. Nonetheless, I do enjoy Appleseed quite a bit, though it doesn't have as much humor as Orion or Dominion Tank Police, nor does it have the cool tech of Ghost in the Shell. And the political in-fighting is interesting, but not as easy to understand, or as clever, as that seen in Ghost in the Shell.
An Appleseed movie was done in 2004, which was entirely CG. I found the movie to be a huge let down. The plot was changed (and simplified) dramatically, and in particular I found that setting it up so that Deunan and Briareos hadn't seen each other in years at the start of the movie was really annoying. One of my favorite parts of Appleseed is the great partners/couple dynamic between these characters, and this change ruined that. It was obviously done to give an easy way to generate dramatic tension, as Deunan wonders if she can trust Briareos and so forth, but it felt like a cheap move. Even ignoring the fact that the plot was switched out entirely, it fails to stand up on its own merits; it's simple, straightforward, and has some annoyingly large holes. Certainly it is difficult to make a movie out of a manga that has not been, and may never be, finished, but I don't find that a good excuse for such a lazy plot.
There was also apparently an OAV put out in 1988, which I have never seen (or had even heard about before recently). "The old movie is not good, particularly the artwork is a major letdown", strangelove reports; apparently they weren't able to get it right either time. It's not terribly surprising, really; after his bad experience with the production of Black Magic M-66, Shirow took a hands off attitude towards the production of the OAV, and while I can't find any confirmation for this, I suspect he took the same approach for the 2004 movie.
There was also an Appleseed game for SNES, which was presumably only available in Japan (as of this writeup, you can download a ROM for it online). It was a side scroller shoot 'em up and apparently sucked quite a bit.
While I would recommend Dominion Tank Police or Ghost in the Shell for first-time Shirow readers, Appleseed is his 'great work' and is highly recommended for anyone who has read and liked his other manga.