We review the current knowledge of the pathophysiology of sickle cell disease (SCD), the clinical complications and the state of the art in SCD diagnostics. Today, a flexible laboratory concept allows the fast and economic clarification of the patients' sickle cell hemoglobin (HbS) status, e.g. additional compound heterozygosities. In contrast to a well-investigated pathophysiology of the disease, factors influencing the severity of symptoms as well as some laboratory findings in SCD still lack a final explanation. In this review, we focus on red cell lysis resistance as an additional diagnostic tool in SCD. There is a need for further studies regarding lysis resistance in blood samples from patients with HbS.