Receptor tyrosine kinases (RTKs) are single-pass transmembrane receptors that possess intrinsic tyrosine kinase catalytic activity in their cytoplasmic domains. RTKs are critical components in signal transduction pathways involved in cellular proliferation, differentiation, migration, and metabolism. This large protein family includes the receptors for many growth factors and for insulin. Ligand binding to the extracellular portion of these receptors results in receptor dimerization, which facilitates trans-autophosphorylation of specific tyrosine residues in the cytoplasmic portion. The phosphotyrosine residues enhance receptor catalytic activity and/or provide docking sites for downstream signaling proteins. Because of the critical roles played by RTKs in cellular signaling processes, their catalytic activity is normally under tight control by intrinsic regulatory mechanisms as well as by protein tyrosine phosphatases. This review will focus on the autoinhibitory mechanisms that modulate RTK catalytic activity.