Sickle cell disease (SCD, OMIM #603903), an autosomal recessively inherited β-hemoglobinopathy, was the first human disorder delineated at a molecular level. The putative single nucleotide mutation in the HBB gene generates an abnormal hemoglobin species, which polymerizes in deoxygenated conditions causing irreversible changes in erythrocyte shape and function. Sickling erythrocytes are in turn responsible for microvascular vaso-occlusion, hemolysis and a systemic vasculopathy in patients. SCD has represented an attractive field for proteomic investigation since its methodological infancy. Clinically actionable biomarkers, especially for the prevention of cerebrovascular complications in children with the condition, are urgently needed and their discovery remains a major challenge. In this issue, Lance and colleagues report of their unbiased proteomic studies on samples from the participants of the landmark prospective, randomized, single-blind SIT trial (NEJM 2014). Their results reveal numerous brain-enriched plasma proteins specific for SCD, and for silent cerebral infarcts in this disorder, and further analyses highlight novel cellular mechanisms behind the brain damage in SCD. Although the goal of identifying reliable biomarker candidates for cerebrovascular complications could not be met, the dataset produced by the authors constitutes a significant contribution to the field and opens new horizons for further clinical and laboratory investigation.