G-protein-coupled 7 transmembrane domain receptors (GPCR-7TMR) represent the largest class of membrane protein drug targets. They respond to a plethora of ligands ranging from small molecules to polypeptide hormones. Upon activation, almost all GPCR-7TMRs undergo desensitization followed by receptor internalization and resensitization. This cycle is crucially important for regulating the signal emanating from the receptor and is tightly linked to the receptor and/or the ligands studied. In this chapter, we describe some of the technical approaches that can be used to study GPCR internalization and trafficking.