Chronic diseases represent a major public health challenge due to their prevalence, steady increase, burden of disease, and the dramatic rise in the risk of disability and dependency. Indeed, these conditions negatively impact patients’ usual and spontaneous physical activity. In turn, physical inactivity exacerbates direct or associated morbidity as well as mortality. In this context, the French National Institute of Health and Medical Research (Inserm) conducted a collective review on the prevention and treatment of 10 groups of chronic diseases through physical activity (PA). The beneficial effects of PA are proven and indisputable. However, identifying the most effective specific physical activity programs for each chronic condition, as well as investigating the determinants of sustained adoption of a more active lifestyle integrated into daily life, remain areas that are only partially addressed. This introductory article presents the main challenges and the reasons justifying regular PA, based on an understanding of the vicious cycle of physical inactivity leading to major muscle deterioration, which in turn aggravates the disease and paves the way for numerous comorbidities (both physical and mental) that negatively impact quality of life, the frequency of hospitalizations, and patient mortality.