Ischemia-reperfusion (I/R) is a well-known pathological condition which may lead to disability and mortality. I/R injury remains an unresolved and complicated situation in a number of clinical conditions, such as cardiac arrest with successful reanimation, as well as ischemic events in brain and heart. Peptides have many attractive advantages which make them suitable candidate drugs in treating I/R injury, such as low toxicity and immunogenicity, good solubility property, distinct tissue distribution pattern, and favorable pharmacokinetic profile. An increasing number of studies indicate that peptides could protect against I/R injury in many different organs and tissues. Peptides also face several therapeutic challenges that limit their clinical application. In this review, we present the mechanisms of action of peptides in reducing I/R injury, as well as further discuss modification strategies to improve the functional properties of bioactive peptides.