The “hyperhemolytic paradigm” (HHP) posits that hemolysis in sickle disease sequentially and causally establishes increased cell‐free plasma Hb, consumption of NO, a state of NO biodeficiency, endothelial dysfunction, and a high prevalence of pulmonary hypertension. The basic science underpinning this concept has added an important facet to the complexity of vascular pathobiology in sickle disease, and clinical research has identified worrisome clinical issues. However, this critique identifies and explains a number of significant concerns about the various HHP component tenets. In addressing these issues, this report presents: a very brief history of the HHP, an integrated synthesis of mechanisms underlying sickle hemolysis, a review of the evidentiary value of hemolysis biomarkers, an examination of evidence bearing on existence of a hyperhemolytic subgroup, and a series of questions that should naturally be applied to the HHP if it is examined using critical thinking skills, the fundamental basis of evidence‐based medicine. The veracity of different HHP tenets is found to vary from true, to weakly supported, to demonstrably false. The thesis is developed that the HHP has misidentified the mechanism and clinical significance of its findings. The extant research questions identified by these analyses are delineated, and a conservative, evidence‐based approach is suggested for application in clinical medicine. Am. J. Hematol. 86:123–154, 2011. © 2010 Wiley‐Liss, Inc.