To date, the only pre-blood stage vaccine to confer protection against malaria in field trials elicits both antigen-specific antibody and T-cell responses. Recent clinical trials of new heterologous prime-boost malaria vaccine regimens using DNA, fowlpox or MVA, have chiefly elicited T-cell responses that have promisingly reduced hepatic merozoites in challenge trials, but failed to protect in field trials. These encouraging results suggest further augmentation of T-cell responses to pre-blood stage antigens might one day contribute to a highly protective vaccine. We envision that a highly protective pre-erythrocytic vaccine will likely be based upon a heterologous prime-boost regimen that induces both appropriate T-cell responses as well as robust and protracted antibody production.