The scientific and clinical challenges that must be addressed and overcome in developing an efficacious HCV vaccine are substantial but not insurmountable. In a short period, considerable progress has been made in the understanding of HCV pathogenesis, epidemiology, and immunology, and the field of vaccinology in general is making very significant strides in developing new ways to activate and modulate immune responses. Advances in DNA vaccines, novel adjuvants, and recombinant protein technology may be keys in developing creative strategies to generate protective immunity against HCV.