On the 15th of April 1983, the Prince and Princess of Wales on their royal tour, departed Spencer Street Station for Ballarat, returning later that afternoon.

Running roughly north–south, Spencer Street forms the western edge of the original Hoddle Grid.

Spencer Street was the site of the first permanent buildings in the settlement now called Melbourne.

[2] With the creation of Docklands in 2000, the rebuilding of Southern Cross railway station in 2006 and the addition of a shopping centre, the area has undergone significant urban renewal.

Many buildings and structures on Spencer Street are listed on the Victorian Heritage Register and/or classified by the National Trust of Australia.