Semaphorins are a large family of molecular cues implicated in neural development and in a variety of functions outside the nervous system. Semaphorin 5A (Sema5A) is a transmembrane semaphorin, containing seven thrombospondin type‐1 repeats, which was recently found to control axon guidance. Here we show that plexin‐B3 is a high‐affinity receptor specific for Sema5A. We further demonstrate that plexin‐B3 activation by Sema5A mediates functional responses in plexin‐B3‐expressing cells (either fibroblasts, epithelial and primary endothelial cells). In addition, Sema5A can trigger the intracellular signalling of the hepatocyte growth factor/scatter factor receptor, Met, associated in a complex with plexin‐B3. We thus conclude that Sema5A is able to elicit multiple functional responses through its receptor plexin‐B3.