Despite decades of research, the question as to whether coffee intake increases the risk of coronary heart disease (CHD) remains controversial. In the current paper, we discuss the acute and long-term cardiovascular effects of coffee, and its major constituents, which could underlie such an association. Experimental studies have shown that administration of coffee or caffeine acutely raises blood pressure, circulating concentrations of (nor)epinephrine, increases arterial stiffness, impairs endothelium dependent vasodilation and inhibits ischemic preconditioning. The adverse effects of chronic coffee consumption on traditional risk factors for CHD are less consistent: although coffee intake slightly increases blood pressure, and plasma concentrations of homocysteine and cholesterol, there is no association with the incidence of hypertension, and a strong negative association with the incidence of type 2 diabetes mellitus. Moreover, common polymorphisms in genes involved in the metabolism of caffeine, catecholamines, homocysteine, and cholesterol can modulate the effect of coffee intake on cardiovascular parameters. Many epidemiological studies have explored the association between coffee drinking and CHD. Most prospective studies have not shown a positive association, whereas case-control studies in general have reported such an association. This discrepancy could be explained by an acute adverse effect of coffee, rather than a long-term adverse effect. We postulate that coffee drinking may have an acute detrimental effect in triggering coronary events and increasing infarct size in selected patient groups, rather than promoting the development of atherosclerosis in the general population, and we propose an alternative approach to explore such an effect in epidemiological studies.