Semaphorins (Semas) are a large family of traditional axon guidance molecules. Through interactions with their receptors, Plexins and Neuropilins, Semas play critical roles in a continuously growing list of diverse biological systems. In this review, we focus on their function in regulating vascular development. In addition, over the past few years a number of findings have shown the crucial role that Semas and their receptors play in the regulation of cancer progression and tumor angiogenesis. In particular, Semas control tumor progression by directly influencing the behavior of cancer cells or, indirectly, by modulating angiogenesis and the function of other cell types in the tumor microenvironment (i.e., inflammatory cells and fibroblasts). Some Semas can activate or inhibit tumor progression and angiogenesis, while others may have the opposite effect depending on specific post-translational modifications. Here we will also discuss the diverse biological effects of Semas and their receptor complexes on cancer progression as well as their impact on the tumor microenvironment.