Chagas disease is a chronic infection by the protozoan parasite Trypanosoma cruzi. The epidemiology of the disease results from the distribution of its arthropod vector, the triatomine bug, throughout Latin America and the southern United States, as well as migration of chronically infected individuals worldwide. In mammals, the parasite cycles through an extracellular infective form and an intracellular replicative form with tropism for cardiac and gastrointestinal (GI) tissues. Over decades, the low-grade inflammatory response can lead to cardiomyopathy and GI dysmotility disorders. This natural history necessitates presentation-dependent diagnostic approaches for clinical workup and risk-based screening, as well as blood donor and organ transplant screening. Implementing effective Chagas disease testing in the U.S. is an increasing topic of interest but is hindered by low provider awareness, few FDA-cleared assays, and limited laboratory capacity for multi-step confirmatory testing. This article provides a clinically focused review of Chagas disease, outlines the current status of clinical testing in the U.S., and reports on new innovations in diagnostics and research that may impact the field.