The microenvironment is critical to the growth of prostate cancer (PCa) in the bone. Thus, for clinical efficacy, therapies must target tumor–microenvironment interactions. Several protein tyrosine kinases have been implicated in the development and growth of PCa bone metastasis. In this review, specific protein tyrosine kinases that regulate these complex interactions, including PDGFR, the EGFR family, c-Src, VEGFR, IGF-1R, FGFR and c-Met will be discussed, with an emphasis on why these kinases are promising therapeutic targets for metastatic PCa treatment. For each of these kinases, small-molecule inhibitors have reached clinical trials. Current results of these trials and future prospects for the use of tyrosine kinase inhibitors for the treatment of PCa bone metastases are also discussed.