African Animal trypanosomosis, caused by blood protozoan parasites transmitted mainly by tsetse flies, represents a major constraint for millions of cattle in sub-Saharan Africa. Exposed cattle include trypanosusceptible indicine breeds, severely affected by the disease, and West African taurine breeds called trypanotolerant owing to their ability to control parasite development, survive and grow in enzootic areas. Cattle trypanotolerance is an emblematic example of local adaptation of livestock to a natural selective pressure embodied by a parasitic disease. Moreover, unravelling biological determinants or genetic bases could be useful to improve animal health and productivity. In order to improve knowledge on biological functions involved in trypanotolerance, we have been conducting different studies based on transcriptomic data, genomic information and the current assessment of immune and metabolic variables. Using RNAseq sequencing of blood cells of five cattle breeds infected by Trypanosoma congolense, we identified bovine genes that were differentially expressed during the infection and we highlighted a strong disturbance in host metabolism and cellular energy production that seems to differentiate trypanotolerant and trypanosusceptible breeds. We are collecting data on immune response and biochemical variables to improve knowledge on pathological processes, and we plan to aggregate these results with genomic data.