Platelet refractoriness is a multifactorial problem that often leads to aggressive measures in an attempt to treat a thrombocytopenic patient. Identification of the underlying causes should allow for prevention and management regimens to improve both transfusion practice and patient outcome. A number of clinical studies have evaluated the relative importance of the various causes of refractoriness. Unfortunately, most are significantly compromised by uncontrolled confounding factors. The causes can be broken down into three categories based on the source of the problem: clinically determined, patient related, or blood bank determined. This breakdown can help to identify appropriate prevention and circumvention measures. Additional causes worthy of increased attention are the platelet transfusion trigger and the tendency for prophylactic transfusion. Improvements in transfusion practice may offer the greatest hope for limiting the complications of platelet transfusion and refractoriness.