Here, we review research on the mechanisms underlying the ability of thrombospondin to promote synaptogenesis and examine its role in central nervous system diseases and drug actions. Thrombospondin secreted by glial cells plays a critical role in synaptogenesis and maintains synapse stability. Thrombospondin regulates synaptogenesis through receptor α2δ-1 and neuroligin 1, and promotes the proliferation and differentiation of neural progenitor cells. It also participates in synaptic remodeling following injury and in the action of some nervous system drugs.