Background Clinical management of two key modifiable risk factors for cardiovascular disease (CVD), hypertension and dyslipidemia, has evolved considerably over the past 40 years, in terms of the focus of therapy, available pharmacologic agents, and therapeutic targets. Materials and methods A brief review of the epidemiology of hypertension and hyperlipidemia and of controlled clinical trials of pharmacologic therapy of these conditions in decreasing cardiovascular events is presented. Results Risk factors for CVD generally do not occur in isolation, and the co-occurrence of hypertension and dyslipidemia, with or without other additional risk factors, greatly increases the risk of CVD. Clinical trials performed in the last 40 years have demonstrated the clinical benefit of treating hypertension and dyslipidemia. Recent trials have shown that intensive, early management of these risk factors provide the greatest clinical benefits. Emerging evidence suggests that lipid management provides clinical benefit in patients at high risk of CVD, regardless of their baseline cholesterol levels, and that lipid-lowering with statin therapy provides additional benefits over antihypertensive therapy alone in high-risk patients with hypertension. It has become evident that the most effective means of reducing CVD risk is the simultaneous management of all modifiable risk factors. Treatment of an individual risk factor can reduce CVD events by approximately 30%, whereas treatment of multiple risk factors can reduce the risk of CVD by more than 50%. However, a large number of patients are not treated or receive suboptimal treatment. Conclusions Overwhelming controlled clinical trial evidence supports the clinical benefit of treating hypertension and hypercholesterolemia. Fixed-dose combination medications for hypertension, and integrative combination therapies containing antihypertensive and lipid-lowering medications in a single pill contribute to better risk factor management with the potential for greater adherence and improved clinical outcomes.