Our work focuses on developing novel pharmacological approaches to prevent and treat alcohol misuse to mitigate its negative impact on individuals and society. Alcohol tolerance, defined as the decrease in effect of alcohol in spite of unaltered concentration is recognized by the Diagnostic and Statistical Manual of Mental Disorders (DSM) as a primary step for escalating intake leading from abuse to dependency in humans. Whether an individual develops drug dependency and addiction is a function of both genetic predisposition and environmental factors. The large conductance voltage- and calcium-activated channel (BK) is a key regulator of neuronal excitability and has been genetically associated to behavioral alcohol tolerance in invertebrates. In mammals the molecular structure of BK channels is complex and composed of alpha and beta subunits, which alter expression and function of the channel in response to ethanol. Different isoforms of the BK channel show variations in alcohol sensitivity. These differences have been linked to alcohol tolerance and increased voluntary consumption. The regulatory mechanisms orchestrating both translation and surface expression of these isoforms in response to ethanol is not well understood and likely underlies the cellular adaptations to long term alcohol misuse.