The present article reviews the status of Chagas disease in Venezuela during the period 2003-2018, based on the detection of Trypanosoma cruzi-infection in 3,343 blood samples of individuals from rural localities and 182 patients referred from health centers to confirm presumptive clinical diagnostic. The study involved samples from 81 rural localities of 17 states located at different regions and ecological life zones of the country. Analysis by parasitological (fresh microscopic observation, hemoculture and Giemsa stained blood smears), serological (DAT, IFAT-polyvalent, IgM, IgG tests) and molecular (PCR) tests, revealed 10.7% seroprevalence and 42.8% T. cruzi-infection, in individuals from rural localities and referred patients, respectively. In both groups T. cruzi-infection was detected at any age, revealing active transmission in children under 10-years-old. Clinical profile detected in referred patients, showed significantly major number of symptoms in orally infected patients than in infected by vectorial route (P<0.01). Genetic characterization of T. cruzi isolates obtained from orally and vectorial transmitted acute Chagas disease in western Venezuela, revealed the circulation of DTUI and DTUIII in the former, and DTUI, DTUII and DTUIII in patients infected by vectorial route. DTUI predominated in both cases, and haplotype Ib was the most frequently found in this genotype. Statistical analysis of clinical profile - T. cruzi DTUs - transmission route relationships did not show association among these variables and, consequently, chagasic patient's clinical condition did not depend of T. cruzi genotype or its route of transmission. In addition, differences in clinical severity may be associated with host susceptibility and/or parasite load received by the human receptor in spite of the T. cruzi genotype itself. The epidemiological implications of the present findings are discussed, and the need for developing efficient tools as well as implementation of urgent and radical changes in the public health policy to control Chagas disease transmission in the Venezuelan territory are suggested.