DNA or nucleic acid vaccines are being evaluated for efficacy against a range of parasitic diseases. Data from studies in rodent model systems have provided proof of principle that DNA vaccines are effective at inducing both humoral and T cell responses to a variety of candidate vaccine antigens. In particular, the induction of potent cellular responses often gives DNA vaccination an immunological advantage over subunit protein vaccination. Protection against parasite challenge has been demonstrated in a number of systems. However, application of parasite DNA vaccines in large animals including ruminants, primates and humans has been compromised by the relative lack of immune responsiveness to the vaccines, but the reasons for this hyporesponsiveness are not clear. Here, we review DNA vaccines against protozoan parasites, in particular vaccines for malaria, and the use of genomic approaches such as expression library immunization to generate novel vaccines. The application of DNA vaccines in ruminants is reviewed. We discuss some of the approaches being evaluated to improve responsiveness in large animals including the use of cytokines as adjuvants, targeting molecules as delivery ligands, electroporation and CpG oligonucleotides.