More than 20 years after the identification of Helicobacter pylori as a human pathogen, gastric cancer continues to be a leading cause of cancer deaths worldwide. Genetic association studies have the potential for helping to identify those at greatest risk for developing gastric cancer subsequent to infection by H. pylori. IL1B promoter polymorphisms have been supported by several meta-analyses as being associated with gastric cancer risk. In this review, we discuss challenges in experimental design of gene association studies in gastric cancer, with attention to gene-environment interactions that may lead to inconsistency in findings across populations.