Coronary heart disease (CHD) reached epidemic proportions during three to four decades, and returned to lower levels after about two decades during the 20th century. The factors which were associated with its increase and decline were blood lipids, blood pressure, smoking, body weight and diabetes. These factors are not exclusive entities. They are both overlapping and interrelated. Thus any analysis of their impact on disease frequency and effects of intervention may be difficult when it comes to making a distinction of each factor’s contribution. All these factors are associated with oxidation and inflammation; essential mechanisms behind atherosclerosis and thrombosis. Two of the factors stand out as the most important explanatory factors as to why the CHD epidemic reached such dramatic levels; the adverse dietary pattern affecting blood lipids, and cigarette smoking. Other factors contributed also but their contribution to changes in disease frequency was more modest. The declining CHD incidence and mortality was subsequent both to declining cholesterol levels and cigarette smoking. These changes coincided with declining intake of saturated fat, but recent meta-analyses do not support a causal role of saturated fat. Industrially produced trans fatty acids often consumed together with saturated fat are likely to have played a more important role as they are directly affecting both oxidation and inflammation. Some of the alleged risk factors are “innocent” bystanders, others have a direct detrimental effect, but they may come in the same package, served at the same meal, or be results of the same lifestyle habit. This will affect the results of the analyses and only underlines the need to assess epidemiological data in a biological context, before one draws firm conclusions on risk factors as direct and causal factors.