Toll-like receptors (TLR) have emerged as key players in the detection of pathogens and the induction of anti-microbial immune response. TLR recognize pathogen-associated molecular patterns, and trigger anti-microbial innate immune responses ranging from the secretion of pro-inflammatory mediators to the increase of natural killer cell cytotoxicity. Besides activating the innate immune response, TLR engagement also shapes the adaptive immune response. Indeed, the broad diversity of signaling pathways initiated by TLR is progressively unraveled. Recent reports suggested that among the anti-microbial defenses they initiate, members of the TLR family can induce apoptosis. This review focuses on this newly described function of TLR, and emphasizes the similarities and differences between the different apoptosis-signaling pathways described downstream of TLR. The functional relevance of TLR-triggered apoptosis is also discussed, as therapeutic applications are likely to ensue in the near future.