The two-digit U.S. Routes follow a simple grid, in which odd-numbered routes run generally north to south and even-numbered routes run generally east to west. (U.S. Route 101 is considered two-digit, its first 'digit' being ten.) Numbers generally increase from 1 in the east to 101 in the west and 2 in the north to 98 in the south. Numbers ending in zero or one (and U.S. Route 2[3]), and to a lesser extent in five, were considered main routes in the early numbering, but extensions and truncations have made this distinction largely meaningless; for instance, U.S. Route 6 was until 1964 the longest route (that distinction now belongs to U.S. Route 20). The Interstate System grid, which increases from west to east and south to north, is intentionally opposite from the U.S. grid, to keep identically numbered routes apart and keeping them from being confused.[4]
Three-digit numbers are assigned to spurs of two-digit routes. For instance, U.S. Route 201 splits from U.S. Route 1 at Brunswick, Maine and runs north to Canada. Not all spurs travel in the same direction as their "parents"; some are only connected to their "parents" by other spurs, or not at all, instead only traveling near their "parents". As originally assigned, the first digit of the spurs increased from north to south and east to west along the "parent"; for example, U.S. Route 60 junctioned, from east to west, U.S. Route 160 in Missouri, U.S. Route 260 in Oklahoma, U.S. Route 360 in Texas, and U.S. Route 460 and U.S. Route 560 in New Mexico. As with the two-digit routes, three-digit routes have been added, removed, extended and shortened; the "parent-child" relationship is not always present. Several spurs of the decommissioned U.S. Route 66 still exist, and U.S. Route 191 travels from border to border, while U.S. Route 91 has been largely replaced by Interstate 15.
Several routes approved since 1980 do not follow the pattern:
* U.S. Route 400, approved in 1994, has no "parent".
* U.S. Route 412, approved ca. 1982, is nowhere near U.S. Route 12.
* U.S. Route 425, approved in 1989, is nowhere near U.S. Route 25.
In addition, U.S. Route 163, approved ca. 1971, is nowhere near U.S. Route 63. The short U.S. Route 57, approved ca. 1970, connects to Federal Highway 57 in Mexico, and lies west of former U.S. Route 81.
While AASHTO guidelines specifically prohibit Interstate Highways and U.S. Highways from sharing a number within the same state[5] (which is why there are no Interstates 50 or 60), the initial Interstate numbering approved in 1958 violated this with Interstate 24 and U.S. Route 24 in Illinois and Interstate 40, Interstate 80, U.S. Route 40 and U.S. Route 80 in California. (US 40 and US 80 were removed from California in its 1964 renumbering.) Some recent and proposed Interstates, some of them out-of-place in the grid, also violate this: Interstate 41 and U.S. Route 41 in Wisconsin (which will run concurrently), Interstate 49 and U.S. Route 49 in Arkansas, Interstate 69 and U.S. Route 69 in Texas, and Interstate 74 and U.S. Route 74 in North Carolina (which will run concurrently).