Cytoskeleton-associated protein-glycine-rich (CAP-Gly) domains are protein-interaction modules implicated in important cellular processes and in hereditary human diseases. A prominent function of CAP-Gly domains is to bind to C-terminal EEY/F-COO-sequence motifs present in α-tubulin and in some microtubule-associated protein tails; however, CAP-Gly domains also interact with other structural elements including end-binding homology domains, zinc-finger motifs and proline-rich sequences. Recent findings unravelled the link between tubulin tyrosination and CAP-Gly-protein recruitment to microtubules. They further provided a molecular basis for understanding the role of CAP-Gly domains in controlling dynamic cellular processes including the tracking and regulation of microtubule ends. It is becoming increasingly clear that CAP-Gly domains are also involved in coordinating complex and diverse aspects of cell architecture and signalling.