Protein phosphorylation lies at the heart of cell signalling, and somatic mutation(s) in kinases drives and sustains a multitude of human diseases, including cancer. The human protein kinase superfamily (the kinome) encodes approximately 50 'pseudokinases', which were initially predicted to be incapable of dynamic cell signalling when compared with canonical enzymatically active kinases. This assumption was supported by bioinformatics, which showed that amino acid changes at one or more key loci, making up the nucleotide-binding site or phosphotransferase machinery, were conserved in multiple vertebrate and non-vertebrate pseudokinase homologues. Protein kinases are highly attractive targets for drug discovery, as evidenced by the approval of almost 30 kinase inhibitors in oncology, and the successful development of the dual JAK1/2 (Janus kinase 1/2) inhibitor ruxolitinib for inflammatory indications. However, for such a large (>550) protein family, a remarkable number have still not been analysed at the molecular level, and only a surprisingly small percentage of kinases have been successfully targeted clinically. This is despite evidence that many are potential candidates for the development of new therapeutics. Indeed, several recent reports confirm that disease-associated pseudokinases can bind to nucleotide co-factors at concentrations achievable in the cell. Together, these findings suggest that drug targeting using either ATP-site or unbiased ligand-discovery approaches should now be attempted using the validation technology currently employed to evaluate their classic protein kinase counterparts. In the present review, we discuss members of the human pseudokinome repertoire, and catalogue somatic amino acid pseudokinase mutations that are emerging as the depth and clinical coverage of the human cancer pseudokinome expand.