The street is a defining border for the Birmingham street grid. East of Center Street, streets and avenues are designated "north" or "south" depending on their location relative to the Railroad Reservation. West of Center Street, both streets and avenues are designated as "west" if they are north of Valley Creek, while roads south of the creek are designated "southwest".
Prior to the 1950s, the street served as a border between residential areas zoned for white and black residents under Birmingham's segregation laws. As that border was challenged by attorney Arthur Shores, and eventually ruled unconstitutional, the district became the focus of a firebombing campaign aimed both at black families moving in and white families selling out. The neighborhood earned the nickname of "Dynamite Hill".
The street is interrupted in several places. Beginning at its southern end at Green Springs Avenue, Center Street South runs due north, past Center Street Middle School to 6th Avenue South. where it bends with the Birmingham street grid. Continuing north by northwest, it jogs over two blocks at 2nd Avenue South in Titusville, then winds across the Norfolk-Southern Railroad tracks into Elyton. It then crosses Valley Creek and bends due north through Graymont, over I-20/59, and ends at Old Bankhead Highway in Fountain Heights.
- 300: former site of William Walker Sr residence
- Valley Creek bridge
- 517: Thirgood Memorial CME Church
- 521: Family Dollar
- 950: former location of Mary Means Monk's residence, bombed on December 21, 1950
- 961: Our Lady Queen of the Universe Catholic Church, bombed on March 21, 1965
- 1100: Hayes-Davis residence, former location of Milton Curry's residence, bombed three times in 1949-1950