The combination of aerobic and resistance training (AER + RES) is recommended by almost every major organization to improve health-related risk factors associated with sedentary behavior. Since the release of the Physical Activity Guidelines for Americans in 2008, several large well-controlled trials and ancillary reports have been published that provide further insight into the effects of AER + RES on health-related outcomes. The current manuscript examines the literature on the effects of AER + RES on major clinical outcomes, including glucose homeostasis, cardiorespiratory fitness (CRF), and muscular strength, as well as other important clinical outcomes, including metabolic syndrome, hypertension, dyslipidemia, and quality of life. Collectively, research suggests that AER + RES and AER or RES alone improves glycemic control and insulin sensitivity compared with continued sedentary behavior. Significant changes in CRF are also observed, suggesting a reduction in cardiovascular disease-related mortality risk. Reduced adiposity, especially abdominal adiposity, and increased strength may also interact with CRF to promote additional health benefits associated with AER + RES. While findings from our review support current physical activity guidelines, a paucity of research limits the generalizability of the results.