In the 10 years since neurotrophic activity was first reported for erythropoietin (EPO), a broad understanding of its multiple paracrine/autocrine functions has emerged. Recent studies firmly establish EPO as a multifunctional molecule, typical of the pliotrophic cytokine superfamily of which it is a member. The realization that EPO activates neuroprotection by multiple mechanisms has identified a generalized system of local tissue protection with EPO as a critical component. Here, the authors characterize the biology of the local tissue-protective system, review data that support this concept, and suggest why non-hematopoietic analogues of EPO may be better choices as therapeutics.