Tuberculosis is a devastating disease that accounts for a high proportion of infectious disease morbidity and mortality worldwide. HIV-1 co-infection exacerbates tuberculosis. Enhanced understanding of the host–pathogen relationship in HIV-1 and Mycobacterium tuberculosis co-infection is required. While reductionist approaches have yielded many valuable insights into disease pathogenesis, systems approaches are required that develop data-driven models able to predict emergent properties of this complex co-infection system in order to develop novel therapeutic approaches and to improve diagnostics. Here, we provide a pathogenesis-focused overview of HIV–TB co-infection followed by an introduction to systems approaches and concrete examples of how such approaches are useful.