Thrombospondins (TSPs) are a family of large, oligomeric multidomain glycoproteins that participate in a variety of biological functions as part of the extracellular matrix (ECM). Through their associations with a number of binding partners, TSPs mediate complex cell-cell and cell-matrix interactions in such diverse processes as angiogenesis, inflammation, osteogenesis, cell proliferation, and apoptosis. It was recently shown in the developing central nervous system (CNS) that TSPs promote the formation of new synapses, which are the unique cell-cell adhesions between neurons in the brain. This increase in synaptogenesis is mediated by the interaction between astrocyte-secreted TSPs and their neuronal receptor, calcium channel subunit α2δ-1. The cellular and molecular mechanisms that underlie induction of synaptogenesis via this interaction are yet to be fully elucidated. This review will focus on what is known about TSP and synapse formation during development, possible roles for TSP following brain injury, and what the previously established actions of TSP in other biological tissues may tell us about the mechanisms underlying TSP’s functions in CNS synaptogenesis.