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Mycobacterium tuberculosis is an important global cause of mortality and morbidity. The major host cell of Mycobacterium tuberculosis is the macrophage, and Mycobacterium tuberculosis is able to subvert the macrophage response in order to survive and replicate. The majority of infected individuals mount an immune response capable of controlling Mycobacterium tuberculosis infection. This requires the cytokines IL-12, TNFα, IL-1 and IFNγ, which promote eradication or control of infection. However, other immune factors, including IL-10 and type I IFN, can inhibit this protective response. In this study we have used microarray analysis to study the temporal response of macrophages to Mycobacterium tuberculosis infection, in an unbiased fashion. In response to Mycobacterium tuberculosis infection, macrophages produced cytokines and chemokines, upregulated genes involved with major histocompatability class I antigen presentation, activated both pro- and anti-apoptotic genes and downregulated many genes involved in cell-division and metabolism. We also observed the early induction of genes regulated by the extracellular-regulated kinase (ERK) MAP kinase pathway, and the upregulation of genes known to be induced by type I IFN, leading us to further investigate the role of these pathways in the macrophage response to Mycobacterium tuberculosis. Both pathways were found to regulate the production of protective and detrimental cytokines in macrophages in response to Mycobacterium tuberculosis infection. In addition, microarray analysis found that these pathways controlled the transcription of numerous genes in response to Mycobacterium tuberculosis infection. Finally, type I IFN was found to inhibit the macrophage response to IFNγ, including IFNγ-mediated killing of Mycobacterium tuberculosis in macrophages, a crucial step in the control of Mycobacterium tuberculosis infection in vivo. We have therefore identified important regulatory mechanisms in macrophages, which are likely have an important role during Mycobacterium tuberculosis infection in vivo.