Even numbered Interstates run east-west, odd numbers run north-south.
Lower numbers are to the south and west of the country and increase as you go north and east (I-5 and I-10 are in Los Angeles, I-80 and I-95 are in New York).
Three-digit numbers represent local feeders in metro areas. Here the rules become a little different. The last two digits represent the parent Interstate, the first, if even, represents a "loop" that encircles a metro area and meets back up with the parent road. Odd numbers feed directly into a city. There are exceptions to this though. Two I can think of off the top of my head are I-495 in New York (The Long Island Expressway) and I-664 in Norfolk, VA (Feeds from I-64 to the Naval Base). Three digit interstates can be duplicated within the country but can appear only once in a state. For example, in addition to the L.I.E., there are also I-495's in Maine, Virginia, Delaware, Massachussets, and Pennsylvania.
Some interesting reading (or not, depending on your point of view):
http://www.kurumi.com/roads/index.html
http://www.snopes.com/autos/law/highways.asp
http://www.exit109.com/~ghealton/wri...terstates.html
http://www.usastar.com/i95/annivsry.htm
There is an urban legend that states that one mile of every five in the Eisenhower Interstate Highway System (the original Interstate system, built in the 50's and marked with special signs) has to be completely flat and straight, with no overpasses or other obstructions. The reason for this is so that in time of war or other national emergency they can be used as runways. This is NOT true. Here the myth is debunked by the Department of Transportation's Federal Highway Administration:
http://www.fhwa.dot.gov/infrastructure/rw00b.htm
-Mikey