The predominant ligand for neurotrophin receptor tropomyosin-related kinase A (TrkA; also known as NTRK1) is nerve growth factor, but other ligands exist, each of which exerts a different cellular outcome. Antonino Cattaneo and colleagues (p. 4445) address how a receptor transduces different ligand-specific signals by studying the dynamics of TrkA at the single-molecule level in the membrane of living cells. Using a new strategy to label TrkA, the authors imaged and tracked single receptor molecules in the absence and presence of a set of diverse biologically relevant ligands. They show that, in the absence of ligands, most of the TrkA receptors are fast-diffusing monomers, with ∼20% moving at least an order of magnitude slower, and ∼4% that were almost immobile within a small area. In the presence of ligands, the populations of slow and/or immobile TrkA receptors are increased, non-immobile trajectories are slower and confinement areas are restricted. The authors next use improved data analysis to investigate ligand-induced TrkA lateral diffusion. Each ligand induced particular changes in receptor diffusion, as well as in the fraction and type of immobile trajectories, with a specific redistribution of TrkA diffusion subpopulations, thus showing a ligand ‘fingerprinting’ effect. This signature depends on the specific ligand-binding affinity for TrkA, the ligand-specific intracellular effectors recruited in the signalling platforms and the ligand-specific formation of signalling and/or recycling endosome precursors. Thus, the dynamics of a receptor in the plasma membrane carries a signature that can be traced back to its specific activation event.