The existence of an ischemic stroke “penumbra” was frst hypothesized by Astrup et al. in 1977 by demonstrating that there was a continuum of “threshold of ischemia” measured by electrical failure (potassium gradient) and reduced cerebral blood flow in the baboon cortical grey matter . The gradient indicated an ischemic core, which is now known to be a mass of dead, unrecoverable tissue at the center of the ischemic infarct. The core is surrounded by oligemic tissue, defned as “Oligemia” tissue with reduced blood flow, but function is unaltered, and ischemic tissue with reduced blood flow. The penumbral tissue, is “at risk” of death tissue with altered potassium release, altered electrical failure and dysfunctional. In 1983, Olsen and colleagues demonstrated that an ischemic penumbra also existed in stroke patients; there was differential distribution of blood flow in non-ischemic, ischemic and hyperemic tissues . The Ischemic Penumbra and Time is Penumbra have been reviewed in some detail by Heiss and Donnan , and two main publications in association with receiving the Johann Jacob Wepfer Award . On this occasion, the 40th anniversary of describing the penumbra, we will take a brief look back at the origin of the stroke penumbra, and forward to review current clinically relevant targets that may arrest penumbral recruitment, and the consequences of such detrimental recruitment. We will also briefly discuss the potential need for multiple forms of therapeutic interventions to maximally promote both short and long term recovery in patients.