Obesity and low cardiorespiratory fitness are both established predictors of cardiovascular disease morbidity and mortality. Whether the protective effects of fitness outweigh the deleterious effects of obesity, however, remains a topic of debate. To extend knowledge of the relative influence of fitness and fatness on cardiovascular disease outcomes, however, attention must be paid to measurement quality. Eliminating inherent bias of self-report and including the highest quality assessments of cardiorespiratory fitness and fatness simultaneously are imperative for head-to-head comparisons. Studies must move beyond body mass index and total body fat percentage to differentiate the heterogenous effects of various adipose tissue depots on cardiovascular risk. Imaging techniques that measure visceral adiposity and other risk-laden ectopic adipose depots while also quantifying cardioprotective adipose depots such as lower body subcutaneous fat and even non-adipose tissues such as skeletal muscle may further illuminate the influence of body composition on cardiovascular health. This review underscores key studies within a large body of literature that provide the foundation for the fit-vs.-fat debate in the context of cardiovascular disease risk, and identifies important considerations for future research.