Until the middle of the 20th century, the building at 45 Flinders Lane housed the industrial equipment and cloth bales of the rag trade. In the early 1990s, with Span Galleries on the ground floor, the lower ground warehouse space was first set up as a commercial gallery. Mary Lou Jelbart and Julian Burnside took over the space, founding fortyfivedownstairs in 2002 with a vision for it to become a unique curated space for both live performance and visual art. For the first five years, exhibitions and theatre productions alternated in the lower ground space.
Following a successful first half decade, in 2007 fortyfivedownstairs expanded and took over the derelict basement of number 45 to create a dedicated performance space on the floor below. Upstairs, the space became two dedicated galleries, in which a curated programme of exhibitions has hung almost constantly since.