Since the development of high-density microarray technology in the late 1990s, global host gene expression changes in response to various stimuli have been extensively studied. More than a dozen peer-reviewed publications have investigated the effect of Leishmania infection in various models since 2001. This review covers the transcriptional changes in macrophage models induced by various Leishmania species and summarizes the resulting impact these studies have on our understanding of the host response to leishmaniasis in vitro. Characterization of the similarities and differences between various model systems will not only further our understanding of Leishmania-induced changes to macrophage gene expression but also identify potential therapeutic targets in the future.