This review focuses on the use of platelets in gene and cell therapy for disease treatments. Platelets are anucleate blood cells produced by megakaryocytes and can be used as delivery systems for therapeutic proteins due to their storage, trafficking, and release capacities. Genetic manipulation of hematopoietic stem cells is carried out to persistently produce genetically engineered platelets that express therapeutic proteins, using tissue-specific promoters to ensure targeted gene expression. Platelet-mediated gene and cell therapy has been evaluated to treat diseases related to hemostasis, thrombosis, and immunity. Human clinical trials also indicated that the novel platelet-mediated ex vivo gene therapy using lentiviral vectors successfully treated a patient with bleeding disorders. In addition, to avoid potentially toxic preconditioning regimens, recent development of in vivo gene therapy using intraosseous delivery of lentiviral vectors showed very promising results in treating both mouse and dog models with hemophilia. These exciting new findings demonstrate the potential of platelet-mediated gene and cell therapy to treat human diseases.