A variety of receptors have been analyzed in sufficient detail to identify sorting motifs. Initial studies focused on the identification of sequences in the cytoplasmic tails of the LDL and transferrin receptors that mediated their internalization. These motifs have since been found in the cytoplasmic domains of a wide variety of receptors and provide for numerous sorting functions. This review will outline the early studies on LDL and transferrin receptors and will then focus on two classes of signaling receptors, receptor tyrosine kinases (EGF and the insulin receptors) and heterotrimeric G-protein coupled receptors (beta2-adrenergic receptors). The identification of sorting motifs and proteins that bind these motifs will be discussed. Importantly, the studies identify a variety of potential targets for modulating the sorting and hence activity of these medically important receptors.