Angiotensin II protein J receptor, APJ, is a type A G protein coupled receptor. Endogenous apelin and elabela peptides stimulate APJ via distinct signalling profiles. A complex signalling map of elabela-stimulated APJ was published in 2022. Dimerization or oligomerization of APJ with itself or other receptor(s) can affect APJ signalling. Apelin has been shown to tolerate mutations and/or modifications at multiple sites without abolishing activity. This offers a great opportunity to design and engineer variants with desired signalling profiles and enhanced resistance to breakdown by peptidases. Several biased agonists with enhanced therapeutic potential have been generated. APJ agonists have therapeutic potential in multiple diseases including cardiovascular, renal, pulmonary and metabolic diseases, and viral infections. APJ antagonists may have therapeutic potential in cancer and retinopathy, and in related diseases in which unwanted angiogenesis is to be halted. A growing understanding of APJ signalling pathways and the robust therapeutic potential of associated ligands for many serious diseases will stimulate the clinical development of APJ ligands.