Tuberculosis remains one of the greatest threats to human health. The causative bacterium, Mycobacterium tuberculosis, is acquired by the respiratory route. It is exquisitely adapted to humans and is a prototypic intracellular pathogen of macrophages, with alveolar macrophages being the primary conduit of infection and disease. However, M. tuberculosis bacilli interact with and are affected by several soluble and cellular components of the innate immune system which dictate the outcome of primary infection, most commonly a latently infected healthy human host, in whom the bacteria are held in check by the host immune response within the confines of tissue granuloma, the host histopathologic hallmark. Such individuals can develop active TB later in life with impairment in the immune system. In contrast, in a minority of infected individuals, the early host immune response fails to control bacterial growth, and progressive granulomatous disease develops, facilitating spread of the bacilli via infectious aerosols. The molecular details of the M. tuberculosis-host innate immune system interaction continue to be elucidated, particularly those occurring within the lung. However, it is clear that a number of complex processes are involved at the different stages of infection that may benefit either the bacterium or the host. In this article, we describe a contemporary view of the molecular events underlying the interaction between M. tuberculosis and a variety of cellular and soluble components and processes of the innate immune system.