I-78 is the main interstate through Bethlehem, connecting it with New York City to the east and Allentown and Harrisburg to the west. The Bethlehem exit is Route 412 (exit 67)); turn right at the bottom of the ramp, regardless of which direction you came from.
I-476, locally referred to as “The Turnpike”, is the main interstate and toll road traveling North-South, going from outside Philadelphia to the Poconos. Get off at the Lehigh Valley Interchange (Exit 56) and continue east on Route 22, which runs through the town. Be aware that this not the Pennsylvania Turnpike, but the Northeast extension of the Pennsylvania Turnpike, but you can go between the two roads without paying the toll. Do not lose your ticket; you will be charged the maximum toll.
US-22, colloquially “22,” is the main highway through Bethlehem and the rest of Lehigh Valley. It runs parallel to I-78 for its length through Bethlehem. Rush hour traffic can be a hassle and the road is altogether congested, and there are local efforts to expand the road, which have not yet resulted in any construction.
PA-378 runs from US-22 in the north to PA-309 in Center Valley. The portion north of the Lehigh River is a freeway, but it turns into a congested city street on the South Side. After Bethlehem, it is a 2 to 3 lane road.