Synthetic biology offers innovative solutions for the treatment of blood disorders, including hemoglobinopathies (e.g., sickle cell disease, β-thalassemia), coagulation disorders (e.g., hemophilia), and immune deficiencies (e.g., SCID), which collectively burden global healthcare systems. Traditional therapies such as blood transfusions and stem cell transplantation face challenges like donor shortages, immune complications, and high costs. This chapter explores how synthetic biology integrates engineering principles with molecular biology to develop advanced therapeutic strategies, including gene therapy, genome editing, synthetic blood substitutes, and engineered T-cell therapies. Gene addition using lentiviral and Adeno-associated virus (AAV) vectors, alongside CRISPR-Cas9-mediated editing, has shown clinical success in correcting genetic defects and reactivating fetal hemoglobin. Synthetic blood substitutes, such as hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbon (PFC) emulsions, address transfusion limitations by providing pathogen-free, universally compatible alternatives. Engineered CAR T-cells have revolutionized hematological malignancy treatment, though challenges like toxicity and antigen escape persist. Nanomedicine and metabolic engineering further enhance these approaches, promising scalable, precise, and accessible treatments. Despite progress, hurdles such as cost, safety, and global equity remain, necessitating continued innovation for widespread clinical adoption.