Semaphorins are mainly known as guidance signals in development, acting through receptors called Plexins. However, their role in cancer is rapidly emerging in the regulation of tumor angiogenesis, tumor growth, cancer cell invasiveness, and metastatic spreading. Intriguingly, activated plexins can transactivate receptor tyrosine kinases, such as MET, VEGFR2, FGFR2, and ERBB2, and lead to distinctive effects in a cell-context-dependent manner. Moreover, certain semaphorins concomitantly target endothelial and cancer cells, and can achieve remarkable inhibition of angiogenesis and tumor growth, associated with anti-metastatic activity. Altogether, these data validate the identification of semaphorin signals as promising therapeutic targets in cancer.