The secretome is the whole of soluble factors and extracellular vesicles (EVs) released ubiquitarian by the cells under certain biological stimuli, especially mesenchymal stem cells (MSCs), both in the quiescent phase or, more markedly, in the inflammatory environment. EVs can be further subdivided into exosomes, microvesicles, and apoptotic bodies depending on their size. The content of the vesicles includes growth factors, transcription factors, protein enzymes, and miRNAs, the latter being responsible for a great part of the EVs modulating activity. This is deeply connected with the concept of MSC being considered as “medicine signaling cells,” that can modify the pathologic microenvironment not as much as directly differentiating on a single tissue, but stimulating the resident cell to repair the lesions more effectively. To further broaden the therapeutic potential of secretome, the concept of “priming the MSC” represents a great improvement: MSCs undergo several stimuli during specific culture conditions, and this allows for extracting a more efficient and specific secretome, opening the landscape of a “next-generation paracrine therapy.” In this chapter, a brief history of secretome is described, followed by the recent “in vitro” observations and the modern preclinical studies involving different pathological settings as cartilage and osseocartilaginous lesions, as well as tendon lesions, up to the new concept of the platelet-derived secretome. The results are promising and fascinating, but further preclinical studies and clinical trials are needed to allow for translating this therapeutic approach to the human clinical situation. Nevertheless, the secretome represents rightfully one of the future therapeutic approaches for orthopaedic tissue engineering.