The role of C-reactive protein (CRP) in atherosclerosis is controversially discussed. Whereas initial experimental studies suggested a pathogenic role for CRP in atherogenesis, more recent genetic data from Mendelian randomization trials failed to provide evidence for a causative role of CRP in cardiovascular disease. Also, experimental results from laboratories all over the world were indeed contradictory, partly because of species differences in CRP biology and partly because data were not accurately evaluated. Here we summarize the published data from experimental work with mainly human material in order to avoid confusion based on species differences in CRP biology. Experimental work needs to be reevaluated after reconsideration of some traditional rules in research: (1) in order to understand a molecule's role in disease it may be helpful to be aware of its role in physiology; (2) it is necessary to define the disease entity that experimental CRP research deals with; (3) the scientific consensus is as follows: do not try to prove your hypothesis. Specific CRP inhibition followed by use of CRP inhibitors in controlled clinical trials may be the only way to prove or disprove a causative role for CRP in cardiovascular disease.