The contribution of proteases to developmental, physiological and pathological processes has been well accepted. Cleavage of matrix proteins is a key requirement for cell migration and remodeling of the extracellular environment. The constant process of matrix turnover is dependent on the delicate balance between degradation and synthesis. In addition, regulated proteolysis also allows for the release and activation of growth factors and cytokines. Similarly to other extracellular matrix proteins, thrombospondins are also targets of proteolysis. While in some cases enzymatic activity is associated with degradation of the protein; in other situations, targeted and selective cleavage offers the means to release polypeptides with either alternative or enhanced function. Here, we provide a summary of the published information related to thrombospondin proteolysis within the context of how proteolysis of extracellular matrix proteins impacts diversification of protein function. We also discuss its biological relevance and potential therapeutic value of thrombospondin proteolysis with particular emphasis on angiogenesis.