Pathogens . 2021 Nov 16;10(11):1493.doi: 10.3390/pathogens10111493 .Chronic manifestations of Chagas disease present as disabling and life-threatening condi-tions affecting mainly the cardiovascular and gastrointestinal systems. Although meaningful research has outlined the different molecular mechanisms underlying Trypanosoma cruzi’<span class="attribute-to-highlight medbox">s</span> infection and the host-parasite interactions that follow, prompt diagnosis and treatment remain a challenge, particu-larly in developing countries and also in those where the disease is considered non-endemic. This review intends to present an up-to-date review of the parasite’<span class="attribute-to-highlight medbox">s</span> life cycle, genetic diversity, virulence factors, and infective mechanisms, as well as the epidemiology, clinical presentation, diagnosis, and treatment options of the main chronic complications of Chagas disease.