It runs roughly east–west and forms the northern boundary of the central business district.

The street was laid out as an extension of the original Hoddle Grid in 1839 and was named after Charles La Trobe.

La Trobe Street is home to a number of precincts and public and private spaces.

Numerous notable buildings and structures on La Trobe Street are listed on the Victorian Heritage Register and/or classified by the National Trust of Australia.

These include: *Also classified by the National Trust In recent years there has been controversy over the number of proposed demolitions for unlisted heritage buildings, including: Two underground railway stations lie beneath La Trobe Street, with Flagstaff station toward the west and Melbourne Central nearer the centre.