The potential of primary prevention to prevent, delay, or ameliorate disease is immense. However, the total spending on preventive services in the United States remains astoundingly small and represents a meager 3.5% of total health care spending. Moreover, training focused on prevention in medical schools is often neglected, and time-constrained primary providers frequently omit effective preventive and early detection measures, or perform them perfunctorily. Indeed, preventable conditions of serious consequences including “premature” mortality, cardiovascular events, and major organ failure are ubiquitous with the global obesity and diabetes epidemics, and the ongoing high prevalence of noxious habits and drug abuse. Although each aspect has been the subject of extensive research, a succinct evidence-based summary is scarce. We have conducted a review of high-quality evidence (systematic reviews, meta-analyses, and practice guidelines) over the last 20 years to extract the best updated recommendations on comprehensive disease prevention and approved screening, briefly citing significant risk reductions by lifestyle interventions, pharmacological prevention, cancer screening, other endorsed screening, immunizations, and issues in the patient-provider interface.