Homologous desensitization occurs when a receptor decreases its response to an agonist at high concentration. It is a process through which, after prolonged agonist exposure, the receptor is uncoupled from its signaling cascade and thus the cellular effect of receptor activation is attenuated.
Homologous desensitization is distinguished from heterologous desensitization, a process in which repeated stimulation of a receptor by an agonist results in desensitization of the stimulated receptor as well as other, usually inactive, receptors on the same cell. They are sometimes denoted as agonist-dependent and agonist-independent desensitization respectively. While heterologous desensitization occurs rapidly at low agonist concentrations, homologous desensitization shows a dose dependent response and usually begins at significantly higher concentrations. 
Homologous desensitization serves as a mechanism for tachyphylaxis and helps organisms to maintain homeostasis. The process of homologous desensitization has been extensively studied utilizing G protein–coupled receptors (GPCRs). While the different mechanisms for desensitization are still being characterized, there are currently four known mechanisms: uncoupling of receptors from associated G proteins, endocytosis, degradation, and downregulation. The degradation and downregulation of receptors is often also associated with drug tolerance since it has a longer onset, from hours to days. It has been shown that these mechanisms can happen independently of one another, but that they also influence one another. In addition, the same receptor expressed in different cell types can be desensitized by different mechanisms.