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The primary purpose of this narrative review was to evaluate the current literature and to provide further insight into the role physical inactivity plays in the development of chronic disease and premature death. We confirm that there is irrefutable evidence of the effectiveness of regular physical activity in the primary and secondary prevention of several chronic diseases (e.g., cardiovascular disease, diabetes, cancer, hypertension, obesity, depression and osteoporosis) and premature death. We also reveal that the current Health Canada physical activity guidelines are sufficient to elicit health benefits, especially in previously sedentary people. There appears to be a linear relation between physical activity and health status, such that a further increase in physical activity and fitness will lead to additional improvements in health status. Physical inactivity is a modifiable risk factor for cardiovascular disease and a widening variety of other chronic diseases, including diabetes mellitus, cancer (colon and breast), obesity, hypertension, bone and joint diseases (osteoporosis and osteoarthritis), and depression.1–14 The prevalence of physical inactivity (among 51% of adult Canadians) is higher than that of all other modifiable risk factors.15 In this article we review the current evidence relating to physical activity in the primary and secondary prevention of premature death from any cause, cardiovascular disease, diabetes, some cancers and osteoporosis. We also discuss the evidence relating to physical fitness and musculoskeletal fitness and briefly describe the independent effects of frequency and intensity of physical activity. (A glossary of terms related to the topic appears in Appendix 1). In a companion paper, to be published in the Mar. 28 issue, we will review how to evaluate the health-related physical fitness and activity levels of patients and will provide exercise recommendations for health. Several authors have attempted to summarize the evidence in systematic reviews and meta-analyses. These evaluations are often overlapping (reviewing the same evidence). Some of the most commonly cited cohorts have been described in different studies over time as more data accumulate (see Appendix 2, available online at www.cmaj.ca/cgi/content/full/174/6/801/DC1). In this review, we searched the literature using the key words “physical activity,” “health,” “health status,” “fitness,” “exercise,” “chronic disease,” “mortality” and disease-specific terms (e.g., “cardiovascular disease,” “cancer,” “diabetes” and “osteoporosis”). Using our best judgment, we selected individual studies that were frequently included in systematic reviews, consensus statements and meta-analyses and considered them as examples of the best evidence available. We also have included important new findings regarding the relation between physical activity and fitness and all-cause and cardiovascular-related mortality.