This review presents recent information about the cross-talk between the tumor cells and the microenvironment in the target organ of metastasis at the premetastatic and metastatic stage. The development of metastatic foci is driven not only by the tumor cells intrinsic properties, but also by the interplay with resident and foreign cells located at particular niches in the target organ. The primary tumor modulates the metastatic target through the production of soluble factors that mobilize cells from distant organs like the bone marrow, which in turn localize in the metastatic niche. There is also strong evidence indicating that some primary tumors induce a fertile ground for the tumor cell at the target organ even before the arrival of the disseminated tumor cell (premetastatic niche). The relationship between the players of the metastatic setting is dynamic and shows a high degree of plasticity. Tumor cells change through the acquisition of genetic and/or epigenetic alterations that provide adaptive advantages and the metastatic niche is remodeled by incoming cell types or newly secreted soluble mediators, as a result a reciprocal dialogue is established that invokes new levels of molecular and cellular complexity. Unraveling the mechanisms that sustain the metastatic niche will allow a better understanding of the biology of the disseminated tumor cell, the design of new therapeutic approaches and, hopefully, the improvement of cancer patients' survival.