Apelin, a regulatory peptide, is an endogenous ligand of the apelin receptor (APJ), which belongs to the G protein-coupled receptor family. The peptide and its receptor are distributed in animal and human tissues, including the cardiovascular and central nervous systems, and studies indicate that apelin signaling could play a role in cytoprotection of cells where it is found. Apelin activity may be modulated by interactions of the APJ receptor with other receptors, resulting in heteromerization. The interaction of the APJ with other receptor systems increases the signaling repertoire of apelin, thereby allowing it to exert a widened degree of control over cellular physiological functions. This article reviews studies which provide evidence for the physiological importance of APJ/Kappa opioid receptor (KOR) heterodimers in several critical cellular processes, including cell proliferation, and results are discussed which support a role of this peptide and the APJ receptor in functioning of the cardiovascular, gastrointestinal and central nervous systems under normal conditions and pathology, as well as novel signal transduction characteristics resulting following the interaction of APJ and KOR. A better understanding of the cellular protective actions of apelin, and the physiological outcomes from interaction of its receptor with other receptor types could lead to new pharmaceutical targets for various diseases affecting among other organs, the heart, the gastrointestinal system and the brain.