• Even numbered ones run east-west.
• Odd numbered ones run north-south.
• Lower numbered ones are south/west of higher numbered ones.
• Primary routes are under 100, and multiples of five are major long-distance routes.
• Auxilliary routes are three digits, with odd first digits for spurs and even ones for roads that rejoin their parent.

And then there's I-99. Instead of being the easternmost highway, it's between I-79 and I-81. By the normal system it would be signed as a spur of I-76 or I-80, but Rep Bud Shuster wanted something more interesting for his district. Instead of letting AASHTO name the new road he decided I-99 would be catchy and got that directly included in the law:

The portion of the route referred to in subsection (c)(9) is designated as Interstate Route I-99.

What I love about this story is how neatly it divides people. Some people hear it and think "how could you so flagrantly disregard the naming system, and for such frivolous reasons!" while others think "I-99 is a much more interesting name than I-576, good for them!" or just "this really doesn't matter very much". Whether you find this story troubling would make a good question on a personality test if it weren't so long.