Caffeine is widely consumed and exhibits varied effects across individuals, largely influenced by genetic factors and environmental conditions. This chapter explores the interindividual differences in caffeine metabolism and its physiological impact, focusing on the roles of the CYP1A2 and ADORA2A genes. The CYP1A2 gene, particularly the rs762551 polymorphism, categorizes individuals as fast, moderate, or slow metabolizers. Fast metabolizers clear caffeine more quickly, experiencing short but intense effects, while slow metabolizers face prolonged exposure, which can lead to heightened sensitivity and side effects. The ADORA2A gene, responsible for encoding the A2A adenosine receptor, is strongly associated with individual variations in caffeine sensitivity, particularly concerning sleep disturbances and anxiety. Polymorphisms like rs5751876 reveal that T/T genotype carriers are more prone to anxiety but less likely to suffer from caffeine-induced insomnia, while C/C genotype carriers are more susceptible to sleep disturbances but less likely to experience anxiety. Environmental factors such as smoking, diet, and medication significantly impact caffeine metabolism. Smoking accelerates caffeine clearance, while certain foods and medications can inhibit it, altering the duration and intensity of caffeine’s effects. This study underscores the importance of considering genetic and environmental factors in understanding caffeine metabolism and its effects. Personalized recommendations based on these factors could optimize caffeine consumption, enhancing performance and well-being while minimizing adverse outcomes. Further research is necessary to elucidate the mechanisms behind these interindividual differences fully.