Heart failure (HF) results in high healthcare costs and burdens for the United States in respects to hospitalizations, therapies, and associated disability. The relative proportion of HF with preserved ejection fraction (HFpEF) compared with HF with reduced ejection fraction (HFpEF) is on the rise; HFpEF has already become the dominant form of HF and it continues to increase. The serious implications of these trends are compounded by a dearth of effective HFpEF therapies. While low physical activity, low cardiorespiratory fitness (CRF), and obesity, are risk factors for HF in general, they particularly predispose to HFpEF. Thus, weight loss and exercise that leads to improved CRF may constitute important opportunities for effective intervention. In this review, we discuss the interplay between physical inactivity, CRF, and obesity in the development of HF, particularly HFpEF, and highlight the current evidence on weight loss and exercise as preventive and therapeutic opportunities. (C) 2017 Published by Elsevier Inc.