Lateral diffusion enables efficient interactions between membrane proteins leading to signal transmission across the plasma membrane. An open question is how the spatio-temporal distribution of cell surface receptors influences the transmembrane signaling network. Here we addressed this issue studying the mobility of a prototypical G protein-coupled receptor, the neurokinin-1 receptor (NK1R) during its different phases of cellular signaling. Attaching a single quantum dot to individual NK1Rs enabled us to follow with high spatial and temporal resolution over long time regimes the fate of individual receptors at the plasma membrane. Single receptor trajectories revealed a very heterogeneous mobility distribution pattern with diffusion constants ranging from 0.0005 to 0.1 μm2/s comprising receptors freely diffusing, confined in 100-600 nm sized membrane domains, as well as immobile ones. A two-dimensional representation of mobility and confinement resolved two major, broadly distributed receptor populations, one showing high mobility and low lateral restriction, the other low mobility and high restriction. We found that about 40% of the receptors in the basal state are already confined in membrane domains and are associated with clathrin. After stimulation with an agonist, additional 30% of receptors became further confined. Using inhibitors of clathrin-mediated endocytosis, we showed that the fraction of confined receptors at the basal state depends on the quantity of membrane-associated clathtrin and is correlated to a significant decrease of the receptors' canonical pathway activity. This shows that the high plasticity of receptor mobility is of central importance for receptor homeostasis and fine regulation of receptor activity.