Trypanosoma cruzi, the causative agent of Chagas’ disease, may sabotage humoral response by affecting B cells at the different stages of its development. The present review highlights the contributions of our laboratory in understanding how T. cruzi hinders B‐cell generation and B‐cell expansion limiting host defence and favouring its chronic establishment. We discuss how homoeostatic mechanisms can be triggered to control exacerbated B‐cell proliferation that favour T. cruzi infection by eliminating parasite‐specific B cells. Specific targeting of evasion mechanisms displayed in T. cruzi infection, as in vivo Fas/FasL blockade or Gal‐3 expression inhibition, allowed us to modulate B‐cell responses enhancing the anti‐parasite humoral immune response. A comprehensive understanding of the biology of the B cell in health and disease is strictly required to devise immunointervention strategies aimed at enhancing protective immune responses during infections.