Listeria monocytogenes is a facultative intracellular pathogen that has the capacity to actively invade and multiply within mammalian cells. Intracellular replication of L. monocytogenes within mononuclear cells was noted in the 1926 publication by Murray and colleagues reporting on this bacterial pathogen for the first time (1). In the 1960s, the seminal work of Mackaness that identified the main actors of cellular immunity against bacterial intracellular pathogens took advantage of the L. monocytogenes intracellular lifestyle as a model (2). In the late 1980s and early 1990s, major L. monocytogenes virulence factors involved in bacterial adaptation to intracellular life were molecularly characterized (3–7) and the precise stages of the L. monocytogenes intracellular life-cycle were morphologically identified (8, 9). Since then, cellular effectors involved in the infection process have been also identified and characterized (10–12). In this article, we review the molecular mechanisms driving L. monocytogenes adaptation to the mammalian host cell intracellular environment.