Since Murry et al. [Murry, C.E., Jennings, R.B., Reimer, K.A., 1986. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 74, 1124-36.] initially reported on the powerful protective effects of ischemic preconditioning (PC), a plethora of experimental investigations have identified varied preconditioning protocols or mimetics to achieve cardioprotection. These stimuli predominantly act via archetypal mediators identified in associated signalling studies (including PI3-K, Akt, PKC, mitochondrial K(ATP) channels). Despite an intense research effort over the last 20 years, there remains a paucity of evidence that this protective paradigm is clinically exploitable. This may arise due to a number of drawbacks to conventional protection, including effects of age, disease, and interactions with other pharmacological agents. This encourages investigation of alternate strategies that trigger protection via unconventional signalling (distinct from conventional PC) and/or mediate sustained shifts in ischemic tolerance in hearts of varying age and disease status. This review considers briefly drawbacks to conventional PC, and focuses on alternate strategies for generating prolonged states of cardiac protection.