In this review, we discuss the 'knowns' and 'unknowns' of host defence towards Mycobacterium tuberculosis. With regard to the 'knowns', both protective and immunopathogenic mechanisms are discussed, including recently discovered new pathways of host defence and inflammatory immunopathology. With regard to the 'unknowns', there will be emphasis on unanswered key questions, accompanied by a perspective on needs and priorities for future research. The role of the inflammatory response and its dysregulation in tuberculosis-related immune reconstitution inflammatory syndrome will also be discussed.