Several drugs have shown benefits in primary and secondary prevention of cardiovascular disease (CVD). Aspirin should be used routinely for the secondary prevention of CVD. Low-dose aspirin should not be used for the primary prevention of CVD in adults ages 60 years and older. Aspirin can be considered for primary prevention in adults ages 40 to 59 years with a 10% or greater 10-year CVD risk. Moderate- to high-intensity statin therapy should be prescribed for most patients with known atherosclerotic CVD, those with a low-density lipoprotein (LDL) cholesterol level of 190 mg/dL or higher, and those ages 40 to 75 years with diabetes or with a 10-year risk of CVD of 7.5% or greater. Newer lipid-lowering drugs have shown benefits in lowering LDL cholesterol levels, but at high cost and with limited evidence of reduction of CVD outcomes. Polypills provide a method to deliver multiple proven drugs at lower cost and to a broader population. Sodium-dependent glucose cotransporter 2 inhibitors or glucagon-like peptide 1 receptor agonists should be added to metformin as the preferred second-line drug in the management of diabetes because of their proven ability to improve cardiovascular outcomes. No supplements have proven benefits in CVD prevention. Omega-3 fatty acids and folic acid have shown benefits when consumed in food.