Immunotherapy relies on the targeting of immune checkpoint receptors and their respective ligands by specific antibodies that bind to the cell surface proteins. The pace of this highly successful clinical advancement has outstripped our cell biological understanding of these receptors. Here, we discuss what is known about their intracellular trafficking itineraries, which determine the bioavailability of these proteins for clinical targeting. Some of them are amongst the shortest-lived membrane proteins (CTLA-4), whilst others can be very stable (PD-L1). We highlight the ubiquitin system, which is key to determining their turnover, as it plays a key role in disposing of misfolded newly synthesised proteins via the ERAD pathway and generating a key signal for endosomal sorting towards lysosomes. In some cases, ubiquitylation can modulate the signalling function of the immune checkpoint receptor, as seen for LAG-3. Immune checkpoint proteins can evade lysosomal degradation by effective recycling to the plasma membrane using highly specialised factors, including CMTM6 (for PD-L1) and LRBA (for CTLA-4). Lastly, we consider how reprogramming the ubiquitin system emerges as an alternative modality in targeting immune checkpoint receptors.