Secretome is how cells communicate with each other. It is composed of extracellular vesicles, specifically small-size exosomes, and larger-size micro vesicles, which are released in the cellular microenvironment after certain stimuli. They can strongly influence the behavior of most resident cells at a repair site after tissue injury. In vitro and preclinical studies have shown a great potential of the intra-articular injection of mesenchymal stem cells secretome when promoting cell differentiation and proliferation, chemoattraction, and immunomodulation at the repair site and further to decrease the fibrotic healing and cell apoptosis. This may therefore lead to efficient cartilage repair and slower progression of osteoarthritis. Moreover, a greater therapeutic potential may be obtained with “secretome functionalization,” by adding anabolic and chondrogenic molecules, specific miRNAs, and specific ligands and receptors to both improve the contents of extracellular vesicles and their ability to bind to specific repair sites in the injured tissue. This can in fact be the start of a new era of cell-free “paracrine” therapy for osteoarthritis.