There is growing interest in the re-emerging interaction between type 2 diabetes (DM) and TB, but the underlying biologic mechanisms are poorly understood despite their possible implications in clinical management. Experts in epidemiologic, public health, basic science, and clinical studies recently convened and identified research priorities for elucidating the underlying mechanisms for the co-occurrence of TB and DM. We identified gaps in current knowledge of altered immunity in patients with DM during TB, where most studies suggest an underperforming innate immunity, but exaggerated adaptive immunity to Mycobacterium tuberculosis. Various molecular mechanisms and pathways may underlie these observations in the DM host. These include signaling induced by excess advanced glycation end products and their receptor, higher levels of reactive oxidative species and oxidative stress, epigenetic changes due to chronic hyperglycemia, altered nuclear receptors, and/or differences in cell metabolism (immunometabolism). Studies in humans at different stages of DM (no DM, pre-DM, and DM) or TB (latent or active TB) should be complemented with findings in animal models, which provide the unique opportunity to study early events in the host-pathogen interaction. Such studies could also help identify biomarkers that will complement clinical studies in order to tailor the prevention of TB-DM, or to avoid the adverse TB treatment outcomes that are more likely in these patients. Such studies will also inform new approaches to host-directed therapies.