Note that a single stretch of road may belong to two different highways. For example, in the northeastern reaches of Lexington, Kentucky, I-64 and I-75 share pavement for about five miles. Likewise, Main Street is all three of US 421, US 25, and US 60 for a few blocks. Crossing the Kentucky River a bit south, near Richmond, I-75, US 25, and US 421 are a single stretch of road.

Note that simply because a road travels 'North/South' per the system above, does not mean that it rigidily travels in that direction. I-85 in North and South Carolina has an enormous 'bow' to the west.

Regarding three-digit interstates: generally if the number starts with an ODD number (105, 305, 505, etc) the route is a spur off of the "parent" interstate. if the number starts with and EVEN number (205, 405, 605, etc) the route is a loop off of the parent road, which will return at some point.

There are exceptions, notably in the SF bay area, where a lack of parent interstates (only Interstate 80) combined with a plethora of interstates, means that the x80 routes don't always follow these rules. Indeed, several don't even intersect I-80!

Regarding route numbers in general: there are exceptions to the rule. The most glaring is Interstate 99 in Pennsylvania, so numbered because the local congressman thought it would be nifty.

Another major "error" is Interstate 238, again in the bay area. As described above, they had a hard time coming up with numbers for the local freeways in the area, so they simply turned what had been CA 238 into I-238. This highway is nowhere near where an Interstate 38 would be, if there were a I-38 in the first place!

There are other exceptions, but these are the most exceptional.

Note that this is the numbering system for the United States Interstate system, not the US Highway system. Interstates are called interstates, and are notated I-###, US highways are called US routes and are notated US-###. There is no consistent numbering system for the US highway system. For instance, US 1 runs more-or-less parallel to I-95 for much of its journey up the East coast.

There's a very strict plan for numbering Interstate routes. The one and two-digit routes are the mainlines, with the even numbered routes going east-west, and the odd routes going north-south. The even routes' numbers increase as you go north, with the odd Interstate roads increasing to the east. The major routes end in 0 or 5. As for three-digit interstates, those that both start and end at a 2-digit route get an even first digit, while those with a dangling end or ends have an odd first digit. Some states do this differently; even 3dis usually return to the parent. California is an example. The last two digits are the parent 2di.

Q: What happened to letter extensions on Interstate highways?
A: AASHTO banned them in 1980 and told state DOTs to think of other numbers. Two still remain on I-35. I-15E in California stayed until 1982.

Q: Why does I-35 split in Dallas and Minneapolis?
A: As stated in the previous question, some Interstates once carried letter suffixes. All but two were changed in 1980. Those two are the I-35 splits in Dallas and Minneapolis, which remain because there was no consensus on what the new numbers would be. The smaller cities, St. Paul and Fort Worth, did not want their Interstate highways "demoted" to 3di's.

Q: Why the heck does I-99 have such a weird number?
A: This has been one of the most contentious questions or topics on the roadgeek newsgroups. Unlike other interstate highways, which have their numbers assigned by AASHTO, I-99's number was assigned in a piece of appropriations legislation sponsored by Rep. Bud Shuster (R-Pa.), through whose district the highway runs. Many of the regulars on m.t.r. and #roadgeek take issue with this highway designation because:
1) Its number was written into law, as described above;
2) Its number is out of place--a highway designated as I-99 should run right along the Atlantic coast; and
3) From its length (under 70 miles), location (in an area where all the available 2di designations are already being used), route (basically, a spur from I-76 to the Altoona/State College area, at least until it connects to I-80), and the fact that it doesn't come close to any interstate other than I-76, an odd 3di designation (such as I-576) would be more appropriate.
As a side note, I-99 also has the distinction of being the only 2 digit interstate that does not have a direct interchange with any other interstate.