Scope: Coffee is associated with a lower risk of cancer, cardiovascular disease, and type 2 diabetes at the population level. However, individual susceptibility to the effects of coffee consumption will cause heterogeneity in health responses between individuals. In this critical review determinants of inter-individual variability in cancer and cardiometabolic health outcomes in response to coffee and caffeine consumption are systematically evaluated. Methods and results: Embase and MEDLINE are searched for observational studies and clinical trials that examined variation in the response to coffee consumption. A total of 74 studies meet the inclusion criteria, which report variation in cancer (n = 24) and cardiometabolic health (n = 50) outcomes. The qualitative analysis shows that sex, BMI, smoking, alcohol intake, menopausal status, and genetic polymorphisms are probable or possible determinants of inter-individual variability in cancer and cardiometabolic health outcomes in response to coffee and caffeine consumption, albeit the majority of studies have insufficient statistical power to detect significant interaction between these factors and coffee consumption. Conclusion: Several genetic and non-genetic determinants of inter-individual variability in the responses to coffee and caffeine consumption are identified, indicating that some of the health benefits of coffee may only occur in a subgroup of subjects.