Part I of this two-part introduction to this Special Issue on the practice of physical therapy in the 21st century outlines the epidemiological basis and rationale for evidence-informed physical therapy practice for addressing contemporary health priorities. This evidence emanates from the definition of health by the World Health Organization (WHO) and the International Classification of Functioning (ICF), and WHO and other international databases on the prevalence of lifestyle conditions. Lifestyle conditions include ischemic heart disease, smoking-related conditions, hypertension and stroke, obesity, diabetes, and cancer. Epidemiological data combined with evidence supporting the effectiveness of noninvasive interventions related to physical therapy to address these priorities (e.g., health education and exercise) are highly consistent with the promotion of health and wellness and the ICF. Given their commitment to exploiting effective noninvasive interventions, physical therapists are in a preeminent position to focus on prevention of these disabling and lethal conditions in every client or patient, their cure in some cases, as well as their management. Thus, a compelling argument can be made that clinical competencies in 21st century physical therapy need to include assessment of smoking and smoking cessation (or at least its initiation), basic nutritional assessment and counseling, recommendations for physical activity and exercise, stress assessment and basic stress reduction recommendations, and sleep assessment and basic sleep hygiene recommendations. The physical therapist can then make an informed clinical judgment regarding whether a client or patient needs to be referred to another professional related to one or more of these specialty areas. The prominence of physical therapy as an established health care profession and its unique pattern of practice (prolonged visits over prolonged periods of time) attest further to the fact that physical therapists are uniquely qualified to lead in the assault on lifestyle conditions. Evidence-based physical therapy practiced within the context of epidemiological indicators (i.e., evidence-informed practice) maximally empowers clinicians to promote lifelong health in every person and in turn, the health of communities. This vision of physical therapy's leading role in health promotion and health care in the 21st century holds the promise of reducing the need for invasive health interventions (drugs and surgery). Part II of this introduction describes evidence-based physical therapy practice within this context of evidence-informed practice.