Toll-like receptors (TLRs) represent the first line of host defense against microbial infection and play a pivotal role in both innate and adaptive immunity. TLRs recognize invading pathogens through the "molecular pattern-recognition", transduce the signals via distinct intracellular pathways involving a unique set of adaptor proteins and kinases, and ultimately lead to activation of transcription factors and inflammatory responses. Among 10 TLRs identified in human, at least two exist in the heart, i.e., TLR2 and TLR4. In addition to their critical role in mediating cardiac dysfunction in septic conditions, emerging evidence suggests that the TLRs can also recognize endogenous ligands and may play an important role in modulating cardiomyocyte survival and in ischemic myocardial injury. In animal models of ischemia-reperfusion (I/R) injury or in hypoxic cardiomyocytes in vitro, administration of a sub-lethal dose of lipopolysaccharide (LPS), which signals through TLR4, reduces subsequent myocardial infarction, improves cardiac functions, and attenuates cardiomyocyte apoptosis. By contrast, systemic deficiency of TLR2, TLR4, or MyD88, an adaptor critical for all TLR signaling, except TLR3, leads to attenuated myocardial inflammation, smaller infarction size, better preserved ventricular function, and reduced ventricular remodeling after ischemic injury. These loss-of-function studies suggest that both TLRs contribute to myocardial inflammation and ischemic injury in the heart although the exact contribution of cardiac (vs. circulatory cell) TLRs remains to be defined. These recent studies demonstrate an emerging role for TLRs as a critical modulator in both cell survival and tissue injury in the heart.