Red blood cell (RBC) transfusion guidelines correctly promote a general restrictive transfusion approach for anemic hospitalized patients. Such recommendations have been derived from evaluation of specific patient populations, and it is important to recognize that engaging a strict guideline approach has the potential to incur harm if the clinician fails to provide a comprehensive review of the patient’s physiological status in determining the benefit and risks of transfusion. We reviewed the data in support of a restrictive or a more liberal RBC transfusion practice, and examined the quality of the datasets and manner of their interpretation to provide better context by which a physician can make a sound decision regarding RBC transfusion therapy. Reviewed studies included PubMed-cited (1974 to 2013) prospective randomized clinical trials, prospective subset analyses of randomized studies, nonrandomized controlled trials, observational case series, consecutive and nonconsecutive case series, and review articles. Prospective randomized clinical trials were acknowledged and emphasized as the best-quality evidence. The results of the analysis support that restrictive RBC transfusion practices appear safe in the hospitalized populations studied, although patients with acute coronary syndromes, traumatic brain injury and patients at risk for brain or spinal cord ischemia were not well represented in the reviewed studies. The lack of quality data regarding the purported adverse effects of RBC transfusion at best suggests that restrictive strategies are no worse than liberal strategies under the studied protocol conditions, and RBC transfusion therapy in the majority of instances represents a marker for greater severity of illness. The conclusion is that in the majority of clinical settings a restrictive RBC transfusion strategy is cost-effective, reduces the risk of adverse events specific to transfusion, and introduces no harm. In anemic patients with ongoing hemorrhage, with risk of significant bleeding, or with concurrent ischemic brain, spinal cord, or myocardium, the optimal hemoglobin transfusion trigger remains unknown. Broad-based adherence to guideline approaches of therapy must respect the individual patient condition as interpreted by comprehensive clinical review.