There are contradictory reports about the effects of obstructive sleep apnea (OSA) on clinical vaso-occlusive events in sickle hemoglobinopathies. The discourse has focused on the possible effects of OSA-associated hypoxemia on hemoglobin S (HbS) polymerization. Advances in understanding the pathogenesis of sickle vaso-occlusion and the physiologic consequences of OSA suggest that the potential for interaction exceeds simple hypoxemia. HbS polymerization, red cell-endothelial cell interactions, hypercoagulability, neutrophil activation and vasoactive factors constitute the multi-pathway model of sickle cell vaso-occlusion. These processes are abnormal in OSA and theoretically these abnormalities may initiate or potentiate vaso-occlusion. If this hypothesis is correct, OSA may convert the clinically benign genetic carrier state of sickle cell trait to a clinically overt disease. Reported clinical events in sickle cell trait are usually related to exposure to relative hypoxia, and are limited to the spleen and renal medulla. Studies to compare the prevalence of events (splenic infarction and hematuria) in sickle cell trait with and without OSA, as well as their relationship to exposure to environmental hypoxia will be a first step in verifying this hypothesis.