Despite decades of effort, an effective malaria vaccine has not yet been developed. Continued issues with the efficacy of the subunit vaccine approach have led to a renewed interest in the use of the whole-parasite vaccine approach for malaria. This approach maximizes the number of antigens presented to the immune system; antigenic diversity will thus have limited impact on efficacy. In this chapter we discuss the use of whole blood-stage parasites in the development of a malaria vaccine. This approach is being developed using killed or attenuated parasites. Attenuation methods include γ-irradiation, genetic deletion/disruption, or chemical treatment of parasites. We discuss these strategies and review the immune responses induced following vaccination. This is an exciting field; however, many challenges remain including issues relating to the use of red blood cells in the vaccine and suitable methods for vaccine storage.