Toll-like receptors (TLRs) play a critical role in the recognition of several pathogens, including Mycobacterium tuberculosis. Mycobacterial antigens recognize distinct TLRs resulting in rapid activation of cells of the innate immune system. Ablation of most of the TLR signalling as in mice deficient for the common adaptor protein MyD88 reveals that TLR is crucial for the activation of an innate immune response. MyD88-deficient mice are unable to clear virulent mycobacteria and succumb to acute necrotic pneumonia. Despite the profound defect of the innate immune response, MyD88 deficiency allows the emergence of an adaptive immunity. These data demonstrate that activation of multiple TLRs contributes to an efficient innate response to mycobacteria, while MyD88-dependent signalling is dispensable to generate adaptive immunity.