This review addresses possible involvement of endogenous digitalis-like sodium pump ligands (SPL) in the mood control and ethanol addiction. Endogenous SPL include cardenolide and bufadienolide classes. Multiple SPL and multiple isoforms of the Na/K-ATPase, one of the key membrane enzymes, comprise a complex regulatory system. In the nervous system, pattern of expression of Na/K-ATPase is based on multiple alpha/beta isoform combinations. Clinical studies demonstrate changes in the activity of Na/K-ATPase in patients with bipolar and unipolar mood disorders. The effects of ethanol on the Na/K-ATPase are concentration-dependent and are associated with both inhibition and activation of enzyme activity. Reinforcing effect of ethanol as well as its voluntary consumption may be affected by digitalis glycosides and endogenous SPL.