Recent studies of proteins containing kinase-like domains that lack catalytic residue(s) classically required for phosphotransfer, termed pseudokinases, have uncovered important roles in cell signalling across the kingdoms of life. Additionally, mutations within pseudokinase domains are known to underlie human diseases, suggesting that these proteins may represent new and unexplored therapeutic targets. To date, few pseudokinases have been studied in intricate detail, but as described in the present article and in the subsequent papers in this issue of Biochemical Society Transactions, several new studies have provided an advanced template and an improved framework for interrogating the roles of pseudokinases in signal transduction. In the present article, we review landmarks in the establishment of this field of study, highlight some experimental challenges and propose a simple scheme for definition of these domains based on their primary sequences, rather than experimentally defined nucleotide-binding or catalytic activities.