Acute chest syndrome (ACS) is associated with prolonged hospitalization and high mortality in sickle cell population. The etiology of ACS is often multifactorial. It is well known that any chest pain that limits ventilation, blood flow or oxygenation establishes the risk of ACS. The independent contributory mechanism is fluid overload, resulting in pulmonary edema. In this report, we present a case of compound heterozygous Hb S/β+ thalassemia in a 32-year-old woman who presented with chest pain complicated by the development of pulmonary edema advancing to acute chest syndrome. We discuss the putative mechanisms might have led to pulmonary edema in this patient including hydration with underlying renal defect, along with a vicious cycle of vascular changes that resulted into pulmonary edema and consequently ACS.