Chronic, excessive alcohol consumption is clearly associated with acute and chronic pancreatitis. However, both clinical and laboratory studies have demonstrated that alcohol consumption alone does not directly cause pancreatitis. Growing evidence suggests that environmental and possibly genetic cofactors must also be present before the mechanisms protecting the pancreas from pancreatitis are circumvented and pancreatitis develops. The discovery that mutations in the cationic trypsinogen gene (R122H, N29I) predisposed to acute and chronic pancreatitis focused attention on possible genetic predispositions. Mutations in the cationic trypsinogen gene, however, are rarely associated with alcoholic chronic pancreatitis. Mutations in the SPINK1 gene (e.g. N34S) provide a threefold increased risk, and cystic fibrosis transmembrane conductance regulator (CFTR) mutations continue to be investigated. However, the major cofactor associated with alcoholic chronic pancreatitis is yet to be identified.