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Cellular signalling is a dynamic process that underlies all aspects of organismal development, function and disease. While signal transduction at the plasma membrane has received a great deal of attention, we now appreciate that activated receptors reside at the plasma membrane for only a small fraction of their life-time. Upon activation by ligand, these receptors are often internalised and sorted into different membrane-bound compartments that allows for enhanced, modified or quenched signalling. Herein we focus on post-endocytic signalling cargo as it traverses compartments including early endosomes, multivesicular bodies, lysosomes, synaptic vesicles or exosomes. Key Concepts Much of cellular signal transduction emanates from endosomal membranes Sorting, trafficking and maturation in endosomes are major regulators of signal transduction. Exosome biogenesis and secretion is an emergent property of cell–cell communication and a target for dysregulation in disease Keywords: endosomes; exosomes; early endosomes; multivesicular bodies; phagosomes; synaptic vesicle; signal transduction; cell–cell communication