In the late nineteenth century, Trypanosoma brucei was discovered as the parasitic protist responsible for Human African Trypanosomiasis (HAT), also known as sleeping sickness. It is transmitted by the bite of the tsetse fly where trypanosomes undergo several steps of differentiation, proliferation and migration that ultimately lead to the production of parasites than can again be infective for a mammalian host. Here, we review four major areas of trypanosome research that saw spectacular progress in knowledge over the last decade. The cell biology of the parasite can now be studied at unprecedented level thanks to the development of 3D electron microscopy, live imaging and super-resolution microscopy, revealing the architecture of all organelles, such as the flagellum that performs multiple essential functions. The omics area has lifted the basic vision of the genome sequence to a highly sophisticated appreciation of gene expression and chromatin organisation, with the ability to interrogate gene function thanks to advanced reverse genetics both at the individual and the global level. These developments were translated in vivo especially via imaging of the infection in the insect and the mammalian host. This resulted in a reconsideration of the life cycle, revealing the critical role of extravascular parasites in mammalian hosts where the skin now appears as a central reservoir for transmission. These findings will have an impact on monitoring and treating the disease in the field, as well as on the programme for elimination of HAT.