Ischemic conditioning induces an endogenous protective mechanism that allows organisms to develop resistance to subsequent insults. The conditioning effect occurs across organs and species. Recently, much attention has been given to remote ischemic limb conditioning due to its non-invasive nature and potential therapeutic applications. While tolerance is induced at the primary injury site (e.g. the heart in cardiac ischemia and the brain in stroke), the site of conditioning application is away from the target organ, suggesting the protective factors are extrinsic in nature rather than intrinsic. This review will focus on the peripheral factors that account for the induction of tolerance. Topics of particular interest are blood flow changes, peripheral neural pathways, humoral factors in circulation, and the peripheral immune system. This review will also discuss how conditioning may negatively affect metabolically compromised conditions, its optimal dose, and window for therapy development.