Stem cells are currently considered to be the best tool for regenerative medicine because of their self-renewal capability and plasticity. It was assumed that the outcomes of cell-based regenerative therapies are achieved due to the engraftment and differentiation of stem cells into targeted cells within the tissues. In recent years, several studies have reported positive outcomes of cell-based therapies despite of insufficient engraftment of transplanted cells. These findings have created a huge interest in the regenerative potential of paracrine factors released from the transplanted stem or progenitor cells. Interestingly, this notion has also led scientists to question the role of proteins in the secretome produced by cells, tissues or organisms under a certain condition or at a particular time for regenerative therapy. Although secretomes can potentially play a vital role in the regeneration process through paracrine signaling, secretome from a particular cell type cannot be the panacea for all diseases. In this review, we attempt to discuss the regenerative potential of secretomes secreted by different cell types for the treatment of different diseases from the molecular point of view. In addition, we also describe the role of pretreatment of cells to produce secretomes enriched with selective paracrine factors that could be designed specifically for a targeted regenerative therapy.