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Conduct a systematic umbrella review to evaluate the relationship of physical activity (PA) with all-cause mortality, cardiovascular mortality, and incident cardiovascular disease (CVD); to evaluate the shape of the dose–response relationships; and to evaluate these relationships relative to the 2008 Physical Activity Guidelines Advisory Committee Report.Primary search encompassing 2006 to March, 2018 for existing systematic reviews, meta-analyses, and pooled analyses reporting on these relationships. Graded the strength of evidence using a matrix developed for the Physical Activity Guidelines Advisory Committee.The association of self-reported moderate-to-vigorous physical activity (MVPA) on all-cause mortality, CVD mortality, and atherosclerotic CVD—including incident coronary heart disease, ischemic stroke and heart failure—are very similar. Increasing MVPA to guidelines amounts in the inactive US population has the potential to have an important and substantial positive impact on these outcomes in the adult population. The following points are clear: the associations of PA with beneficial health outcomes begin when adopting very modest (one‐third of guidelines) amounts; any MVPA is better than none; meeting the 2008 PA guidelines reduces mortality and CVD risk to about 75% of the maximal benefit obtained by physical activity alone; PA amounts beyond guidelines recommendations amount reduces risk even more, but greater amounts of PA are required to obtain smaller health benefits; and there is no evidence of excess risk over the maximal effect observed at about three to five times the amounts associated with current guidelines. When PA is quantified in terms of energy expenditure (MET·h·wk−1), these relationships hold for walking, running, and biking.To avoid the risks associated with premature mortality and the development of ischemic heart disease, ischemic stroke, and all-cause heart failure, all adults should strive to reach the 2008 Physical Activity Guidelines for Americans.