The global prevalence of human immunodeficiency virus type-1 (HIV-1) and emerging infections with dengue, West Nile virus (WNV) and Leishmania donovani have increased greatly in recent decades, with rapidly growing numbers of people infected with these pathogens.  Currently, no vaccine is available for the prevention of these infections, and no effective drugs are available to treat many of these blood-borne diseases. This article presents the novel concept of inducing an effective innate host defense response against these infections, which can be transmitted by blood transfusion or insect vectors. The proposed concept is supported by experimental evidence that the induction of an endogenous cytoprotective factor, heme oxygenase-1 (HO-1), by its physiological regulator hemin (the active component of an FDA-approved drug), promotes cellular protection against HIV-1, WNV, dengue, and Leishmania donovani infections. Thus, regardless of the type of pathogenic infection, HO-1 induction may provide a potentially novel, safe, and alternative natural therapeutic strategy for the treatment of a number of existing and emerging transfusion-transmitted diseases. In view of the continued challenges due to emerging drug-resistant mutants, this approach may particularly be useful for treating infections for which no vaccine is currently available, or no safe and effective drug is available to treat the diseases caused by such pathogens.