Drug addiction is a major psychiatric disorder with a neurobiological basis that is still insufficiently understood. Initially, non-addicted, controlled drug consumption and drug instrumentalization are established. They comprise highly systematic behaviours acquired by learning and the establishment of drug memories. Ca2+/calmodulin-dependent protein kinases (CaMKs) are important Ca2+ sensors translating glutamatergic activation into synaptic plasticity during learning and memory formation. Here we review the role of CaMKs in the establishment of drug-related behaviours in animal models and in humans. Converging evidence now shows that CaMKs are a crucial mechanism of how addictive drugs induce synaptic plasticity and establish various types of drug memories. Thereby, CaMKs are not only molecular relays for glutamatergic activity but they also directly control dopaminergic and serotonergic activity in the mesolimbic reward system. They can now be considered as major molecular pathways translating normal memory formation into establishment of drug memories and possibly transition to drug addiction. Ca2+/calmodulin-dependent protein kinases (CaMKs) translate glutamatergic activation into synaptic plasticity during learning and memory formation.Addictive drugs increase CaMK activity, foremost that of αCaMKII.The CaMKII increase is a necessary prerequisite for the learning and consolidation of drug memories.During withdrawal, CaMKII activity declines, but rises again during reinstatement of drug seeking and consumption.CaMKs control dopaminergic and serotonergic activity in the mesolimbic system.