Anti-craving compounds have recently been registered for relapse prophylaxis in weaned alcoholics in various European countries (acamprosate), and in the United States (naltrexone). Acamprosate, the Ca2+-salt of N-acetyl-homotaurinate, interacts with NMDB receptor-mediated glutamatergic neurotransmission in various brain regions and reduces Ca2+ fluxes through voltage-operated channels. The opioid receptor antagonist naltrexone most likely interferes with alcohol-induced reinforcement via the block of opioid receptors. In this article Rainer Spanagel and Walter Zieglgansberger discuss the pivotal role of incremental neuroadaptation to alcohol and alcohol-associated stimuli for craving, and the possible mechanisms of action underlying the anti-craving properties of acamprosate and naltrexone.