FKBP51 (FKBP5 Official Symbol) is large molecular weight member of the FK506 binding protein family, a subfamily of the immunophilin proteins. FKBP51 exerts multiple biological functions in the cell, including modulation of steroid hormone response, immune regulation, cell proliferation, regulation of pAkt levels and control of NF-κB activation. Several lines of evidence support a role for this protein in cancer biology, especially in resistance to chemo- and radio-therapy. Recent research studies highlighted functions of FKBP51 in promoting the epithelial to mesenchymal transition (EMT) transdifferentiation program in melanoma. This process, which is classically regulated by Transforming Growth Factor (TGF)-β, enables cancer cells to disseminate from primary tumors and spread to distant locations, acquiring resistance to therapy and self-renewal capability. This last, in turn, is crucial to their subsequent expansion at sites of dissemination. The aim of the present article is to review recent literature data that involve FKBP51 in the mechanisms that switch the TGF-β from a tumor suppressor to a pro-metastatic invader.