Red blood cell levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are a reflection of tissue levels and are determined by a complex interplay of metabolism and nutrition. Low levels of EPA+DHA in erythrocytes are associated with increased risk for sudden cardiac death. If levels of EPA+DHA in erythrocytes are determined using a strictly defined and standardized method, then the clinical significance of differing levels (previously defined in major research studies using this methodology) may be understood and applied in patient care. The Omega-3 Index, which is the EPA+DHA content of erythrocytes expressed as a percent of total identified fatty acids, was originally suggested as a marker of increased risk for death from coronary heart disease, but it can also be viewed as an actual risk factor, playing a pathophysiologic role in the disease. Optimal levels appear to be 8% or greater. At this stage of its development, the Omega-3 Index appears to fulfill many of the requirements for both a risk marker and a risk factor. Using the Omega-3 Index in the design of clinical studies might allow for a more efficient use of research resources.