U.S. 50 runs east–west across the southern portion of the state, between Interstate 70 to the north and Interstate 64 to the south. Along many portions of U.S. 50, the road has been moved onto either a bypass or an expressway.
Much of U.S. 50 is a two-lane highway, but portions around Lawrenceville, IL and Vincennes, IN are configured as a four-lane, limited access bypass, built to interstate standards in the 1960's. Another modern bypass portion between O'Fallon, IL and IL-127 shows evidence of a four-lane right of way as each bridge is paralleled by a second that remains unused and the graded road bed for additional lanes is visible. This is because it was originally meant to be the route of Interstate 64 until political leaders lobbied for and secured a more southerly route.