This chapter discusses the reasoning behind clinical decisions for most individuals with chronic Trypanosoma cruzi infection (i.e., seropositive adults). It covers the goals and suggested strategies for diagnosis and treatment across the clinical spectrum of chronic Chagas cardiomyopathy (CCC), as the most relevant outcome for this population. Uncertainty surrounds most clinical decisions for individuals at risk or with diagnosis of CCC. For such complex, neglected tropical disease, it has been very challenging to produce rigorous, longitudinal studies testing modern prognosis and therapy tools and recording a sufficient number of clinical events. As a condition, being seropositive increases the risk of mortality at any clinical stage. Since the emergence of CCC is relatively infrequent, but substantial clinically, ruling out disease is critical upon serology diagnosis. We therefore propose a high-sensitivity initial approach, combining B-type natriuretic peptide with an electrocardiography (with a conventional ECG, adding a continuous monitoring for at least 1 h when negative). For those diagnosed with CCC, we propose to make use of Rassi’s (the only externally validated) scale for a risk-oriented clinical staging and disease monitoring. As high-risk individuals, treatment should be considered always, paralleling complexity with CCC staging. Those with early or no disease will probably derive more benefit from trypanocidal therapy (TT) in order to clear parasitism and may not need another measure while CCC-free. A special, very important case is that of seropositive women in childbearing age, who should receive TT to prevent congenital transmission in future pregnancies. Adjuvant, proven treatment for heart failure from other origins is increasingly important for CCC patients and should be offered aggressively from early stages as an attempt to prevent its devastating complications and mortality.