The topic of host cell death response upon Mycobacterium tuberculosis (Mtb) infection has been a controversial one [1]. Recent findings demonstrate that one of the important confounding factors was most likely the fact that while Mtb inhibits host cell apoptosis induction early during the infection it clearly induces a necrotic form of cell death during later infection stages [2, 3]. This bi-phasic intracellular lifestyle in regard to host cell death manipulation is emerging as a common theme shared with other facultative and obligate intracellular bacterial pathogens such as Chlamydia and Legionella [4-6]. Accordingly, the list of discovered bacterial proteins involved in host cell apoptosis inhibition is growing [7, 8]. At the same time it is clearly beneficial for the resistance of the host to overcome the bacterial apoptosis block during the early stage of the infection [9-11]. Hence, host cell components have evolved to recognize intracellular pathogens and mediate host cell apoptosis induction if necessary [12]. There have been several reviews on the various aspects of the host cell death response upon Mtb infection [1, 3, 13-15]. Thus in this chapter I will focus on the pathogen side of the equation and describe the tremendous progress that has been made in the identification and characterization of Mtb genes involved in manipulation of host cell death pathways.