The development of new approaches for the treatment of alcohol dependence (AD) may improve patient outcomes. One very successful treatment approach for addictive behaviors is substitution maintenance therapy which is most effective for the treatment of opioid and nicotine dependence. Jonathan Chick and David Nutt have discussed potential substitution therapies for AD a decade ago (Chick & Nutt, 2012) but otherwise this treatment approach has received only very little attention in the alcohol research field. Here we provide a theoretical and clinical perspective for substitution maintenance therapy for AD, explain the molecular rationale for alcohol substitution, and discuss drugs or approved medications for other indications that may be conceptualized as substitution therapies for AD with a focus on compounds with clinical evidence of efficacy in the long-term treatment of AD.