Alcohol-associated acute and chronic pancreatitis occur in a minority of alcohol users, suggesting that most drinkers are protected from pancreatic diseases while a subset is susceptible. Ongoing studies suggest that the pathophysiology is complex and can involve multiple genetic and environmental pathways and stochastic events. Both rat models and human genetic epidemiology studies have been used to understand susceptibility and modifying factors in humans. Rat studies suggest that different types of altered pancreatic physiology occur depending on dose, they occur rapidly and that alcohol changes the immune response to recurrent pancreatic injury. Human studies suggest that PRSS1 and SPINK1 mutation increase the pancreas’ susceptibility to alcohol-associated pancreatitis, and that tobacco smoking, and some factors, affect disease progression.