In mammals, the circadian hormone melatonin targets two seven-transmembrane-spanning receptors, MT1 and MT2, of the G protein-coupled receptor (GPCR) super-family. Evidence accumulated over the last 15 yrs convincingly demonstrates that GPCRs, classically considered to function as monomers, are actually organized as homodimers and heterodimerize with other GPCR family members. These dimers are formed early in the biosynthetic pathway and remain stable throughout the entire life cycle. A growing number of observations demonstrate that GPCR oligomerization may occur in native tissues and may have important consequences on receptor function. The formation of MT1 and MT2 homodimers and MT1/MT2 heterodimers has been shown in heterologous expression systems at physiological expression levels. Formation of MT1/MT2 heterodimers remains to be shown in native tissues but is suggested by the documented co-expression of MT1 and MT2 in many melatonin-sensitive tissues, such as the hypothalamic suprachiasmatic nuclei, retina, arteries, and adipose tissue. Considering that multiple GPCRs are expressed simultaneously in most cells, the possible engagement into heterodimeric complexes has to be considered and taken into account for the interpretation of experimental data obtained from native tissues and knockout animals.