Caffeine use is widespread in sport, with a strong evidence base demonstrating its ergogenic effect. Based on existing research, current guidelines recommend ingestion of 3-9 mg/kg approximately 60 min prior to exercise. However, the magnitude of performance enhancement following caffeine ingestion differs substantially between individuals, with the spectrum of responses ranging between highly ergogenic to ergolytic. These extensive inter-individual response distinctions are mediated by variation in individual genotype, environmental factors, and the legacy of prior experiences partially mediated via epigenetic mechanisms. Here, we briefly review the drivers of this inter-individual variation in caffeine response, focusing on the impact of common polymorphisms within two genes, CYP1A2 and ADORA2A. Contemporary evidence suggests current standardised guidelines are optimal for only a sub-set of the athlete population. Clearer understanding of the factors underpinning inter-individual variation potentially facilitates a more nuanced, and individually and context-specific customisation of caffeine ingestion guidelines, specific to an individual's biology, history, and competitive situation. Finally, we identify current knowledge deficits in this area, along with future associated research questions.