Exocrine pancreatic cancer remains a major cause of cancer death in Western populations. Despite many efforts, little is known about its etiology. Tobacco is the only established cause, although the proportion of cases of exocrine pancreatic cancer attributed to it is only 30%. A family history of pancreatic cancer accounts for 10% of the cases of this disease. A large proportion of cases are due to yet unrecognized factors. The combined contribution of genetic susceptibility and environmental factors has rarely been considered. A higher risk of exocrine pancreatic cancer has been observed for patients with hereditary pancreatitis who smoked. It has also been suggested that CFTR mutations and alcohol could interact in the development of exocrine pancreatic cancer. Common variants in a large number of genes could act as low-penetrance alleles. Little is known about their role as susceptibility markers for exocrine pancreatic cancer, except for metabolic enzymes. A few studies have assessed the association between polymorphisms in these genes and exocrine pancreatic cancer. Surprisingly, none of them observed an interaction with tobacco consumption. The reality may be more complex; exocrine pancreatic cancer is genetically heterogeneous and it could involve many somatic and heritable mutations. Gene-gene interactions and endogenous factors, among others, can contribute to tumor development. Future epidemiological studies should consider all of these aspects together.