Conjugation of protein antigen with immunostimulatory oligonucleotides creates a potent immunogen that elicits antigen-specific antibody responses, a Th1-biased cytokine profile, and CD8 cytotoxic T lymphocyte activity. The wide range of humoral and cellular immune responses induced by these conjugates suggests they can be used to create effective vaccines against infectious pathogens and tumors and to beneficially modulate the immune responses seen in allergic diseases. This review summarizes the available data on the use of antigen-oligonucleotide conjugates and discusses their potential use for the treatment of infectious, oncologic, and allergic diseases in humans.