Everyone knows how to make a fist. Surprisingly few people know how to use it properly. The basic primal instinct during a physical altercation is to swing your arms wildly with hopes of bludgeoning your opponent in a lucky blow. There are right ways to use your natural weapons and there are wrong ways. The aforementioned, as you may guess, is one of many wrong ways.
Make a fist. Go on, do it. Look at it from the top down, the back of your hand facing up. You'll notice that your middle finger knuckle lines up with your radius and ulna in a straight line until your elbow. When the arm is fully extended, this line goes from the knuckle all the way up the humerus to the shoulder ending with the scapula. This straight line is also present for you first finger knuckle. Now look at your pinky finger and ring finger lines. The metacarpals for these knuckles must slant towards the wrist. They have no reinforcement from the arm bones. When striking properly, only the first and middle knuckles should be used.
When performed properly, the shock of the impact travels up the arm, diffusing into the tissue and weakening until it is finally absorbed easily by the shoulder joint with minimal harm. If a punch is landed on the two "no-no" knuckles, (the ring and pinky) the shock is coming in straight onto a diagonal path. Often the joint of the metacarpal and the wrist is broken. This is referred to as a "Boxer's break". It is very painful, it happens esily, and it takes a long time to heal.
Another common mistake made when striking at someone with fists is the trajectory of the fist itself. Often the atacker will swing in a wide arc. This swing is different from a hook punch used in boxing in that the wide swing has the arm loose (usually almost straight) and using centrifugal velocity. A hook punch has the elbow at roughly a 90 degree angle held rigid while the torso of the attacker is pulled in a twist motion.
However, the most effective punch is the straight punch. Using the fist as previously mentioned, start the attack with the fist upside down near the hip (thumb facing up, back of hand facing down). Push the fist outward very quickly, turning the fist quickly right-side-up at the point of impact. This creates torque which enhances the force. Do not snap your punch to the end of your elbow range. The punch should stop where your elbow is in the position where it hangs when your arms are relaxed by your sides. This prevents both your opponent being able to pull you off balance and your opponent being able to break your elbow easily.
To finish, I would not advise hitting someone until you have no choice. Even when your enemy steals your girlfriend/boyfriend, you still have the option not to hit them, even if you don't think you do. One way to prevent the almost unavoidable pain resulting from the impact on your knuckles is to use regular Takeshewadi training. Have fun rumbling.