With iron at its core, the tetrapyrrole heme ring is a cardinal prosthetic group made up of many proteins that participate in a wide array of cellular functions and metabolism. Once released, due to its pro-oxidant properties, free heme in sufficient amounts can result in injurious effects to the kidney and other organs. Heme oxygenase-1 (HO-1) has evolved to promptly attend to such injurious potential by facilitating degradation of heme into equimolar amounts of carbon monoxide, iron, and biliverdin. HO-1 induction is a beneficial response to tissue injury in diverse animal models of diseases, including those that affect the kidney. These protective attributes are mainly due to: (i) prompt degradation of heme leading to restraining potential hazardous effects of free heme, and (ii) generation of byproducts that along with induction of ferritin have proven beneficial in a number of pathological conditions. This review will focus on describing clinical aspects of some of the conditions with the unifying end-result of increased heme burden and will discuss the molecular mechanisms that ensue to protect the kidneys.