Homocysteine is an independent cardiovascular disease (CVD) risk factor modifiable by nutrition and possibly exercise. While individuals participating in regular physical activity can modify CVD risk factors, such as total blood cholesterol levels, the impact physical activity has on blood homocysteine concentrations is unclear. This review examines the influence of nutrition and exercise on blood homocysteine levels, the mechanisms of how physical activity may alter homocysteine levels, the role of homocysteine in CVD, evidence to support homocysteine as an independent risk factor for CVD, mechanisms of how homocysteine increases CVD risk, and cut-off values for homocysteinemia. Research examining the impact of physical activity on blood homocysteine levels is equivocal, which is partially due to a lack of control for confounding variables that impact homocysteine. Duration, intensity, and mode of exercise appear to impact blood homocysteine levels differently, and may be dependent on individual fitness levels.