Heptahelical G-protein-coupled receptors are the most diverse and therapeutically important family of receptors, playing major roles in the physiology of various organs and tissues. They couple their ligand binding to G-protein activation, which then transmits intracellular signals. G-protein signaling is terminated by phosphorylation of the receptor by the family of G-protein-coupled receptor kinases (GRKs), followed by arrestin (Arr) binding, which uncouples the phosphorylated receptor from the G-protein and subsequently targets the receptor for internalization. Moreover, Arrs can transmit signals in their own right during receptor internalization. Genetic polymorphisms in receptors, as well as in GRK and Arr family members per se, which affect regulation of receptor signaling and function, have just started being identified and characterized. The present review will discuss what is known so far in this evolving field of GRK/Arr pharmacogenomics, as well as highlight important areas likely to produce invaluable information in the future.