Despite the wide palette of clinically available investigative tools, not all deep molecular phenomena governing the cardiovascular system can be studied on living humans. Therefore, a reasonable alternative is to explore such phenomena on animal models, given that the two-circuits centered on a tetra chamber heart practically did not evolve since the crocodilians. This review presents our two decades-long experience with mouse, rat and dog models of Chagas disease, metabolic syndrome, post ischemic heart failure, and pulmonary hypertension. We studied also the transcriptomic consequences of cell treatment of Chagas and ischemic cardiomyopathies, genetic engineering, and exposure to hypobaric hypoxia, oxygen deprivation, low salt and high fructose diets. Among others, the investigations revealed heart transcriptomic sex dichotomy and inter-chamber differences, as well as changes in the subcellular localization of the heart rhythm determinants: connexin43, plakophilin-2, N-cadherin and plakoglobin during the female estrogen cycle. Use of these animal models considerably enriched our understanding of the cardiovascular system pathophysiology.