Molecular oncogenic events associated with PC initiation and progression to a locally invasive disease stage and bone metastasis and novel targeting therapies. The scheme shows the PC initiation through the accumulation of genetic and epigenetic alterations in prostate-resident adult stem cells resulting in their malignant transformation into tumorigenic PC stem/progenitor cells also designated as PC-initiating cells. The transformation of tumorigenic PC stem/progenitor cells into migrating PC stem/progenitor cells, which may be induced through the sustained activation of distinct growth factor signaling pathways during the EMT program and PC progression, is also shown. Furthermore, the possible invasion of certain tumorigenic and migrating PC stem/progenitor cells in the activated stroma, which may lead to their dissemination through the peripheral circulation at distant sites including bones along chemoattractant ligand gradient systems such as SDF-1/CXCR4, is illustrated. The activation of metastasis-initiating cells under specific microenvironmental conditions prevalent at bone induced via the release of diverse paracrine growth factors and cytokines by fibroblasts and bone cells, and that is associated with the formation of secondary tumor formation at bone, is also illustrated. The release of growth factors and cytokines such as SHH, TGF-α, TGF-β and MIC-1 by PC cells that can induce in a paracrine manner the differentiation of either osteoblast or osteoclast precursors into osteoblasts or osteoclasts, thereby causing the osteoblastic lesion (new bone formation) or osteolytic lesion (bone destruction) in certain cases, is also indicated. In addition, the molecular targeting of distinct gene products deregulated in PC- and metastasis-initiating cells, which might constitute a potential strategy to improve current treatments, eradicate the total PC cell mass and prevent disease relapse, is also indicated.