Sickle cell disease (SCD) is the most common monogenic hematologic disorder and is essentially congenital hemolytic anemia caused by an inherited point mutation in the β-globin on chromosome 11. Although the genetic basis of SCD was revealed as early as 1957, treatment options for SCD have been very limited to date. Hematopoietic stem cell transplantation (HSCT) was thought to hold promise as a cure for SCD, but the available donors were still only 15% useful. Gene therapy has advanced rapidly into the 21st century with the promise of a cure for SCD, and gene editing strategies based on the cluster-based regularly interspaced short palindromic repeat sequence (CRISPR)/Cas9 system have revolutionized the field of gene therapy by precisely targeting genes. In this paper, we review the pathogenesis and therapeutic approaches of SCD, briefly summarize the delivery strategies of CRISPR/Cas9, and finally discuss in depth the current status, application barriers, and solution directions of CRISPR/Cas9 in SCD. Through the review in this paper, we hope to provide some references for gene therapy in SCD.