Sickle cell disease (SCD) is an autosomal recessively inherited β-hemoglobinopathy causing a sickling hemoglobin (HbS) to be expressed in the erythrocyte. Due its unique biophysical properties and tendency to form polymers in deoxygenated conditions, HbS causes dramatic erythrocyte deformation and damage ultimately leading to diffuse hemolysis, vasco-occlusion, and vasculopathy in affected individuals. Albeit SCD was the first molecular disease identified in the human several decades ago, the progress in caring for patients with SCD has been globally limited and faces considerable biological, medical, psychological, and economic challenges. The aim of this review is to illustrate the opportunities lying ahead for proteomic discovery in SCD. It also establishes a tentative conceptual framework for clinically oriented investigations. The ultimate target is the translation of findings into validated and actionable improvements at the bedside. Thanks to significant technological advances, proteomics is poised to play an important role for patients affected by hematological disorders, and SCD could be a paradigm for impactful research.