The semaphorins constitute a large family of molecular signals with regulatory functions in neuronal development, angiogenesis, cancer progression and immune responses. Accumulating data indicate that semaphorins might trigger multiple signalling pathways, and mediate different and sometimes opposing effects, depending on the cellular context and the particular plexin-associated subunits of the receptor complex, which can include receptor-type or cytoplasmic tyrosine kinases such as MET, ERBB2, VEGFR2, FYN, FES, PYK2 and SRC. It has also been shown that a specific plexin can alternatively associate with different tyrosine kinase receptors, eliciting divergent signalling pathways and functional outcomes. Tyrosine phosphorylation is a pivotal post-translational protein modification that regulates intracellular signalling. Therefore, phosphorylation of tyrosines in the intracellular domain of plexins could determine or modify their interactions with additional signal transducers. Here, we discuss the potential relevance of tyrosine phosphorylation in semaphorin-induced signalling, with an emphasis on its probable role in dictating the choice between multiple pathways and functional outcomes. The identification of implicated tyrosine kinases will pave the way to target individual semaphorin-mediated functions.