Adjuvants are components that when added to subunit antigen (Ag) vaccines boost their immunogenicity and thus immune efficacy. However, there are few adjuvants that are approved for clinical use resulting in a critical need for the development of safe and effective adjuvants for use in both prophylactic and therapeutic vaccines. The paucity of appropriate adjuvants is more chronic for the development of therapeutic vaccines for cancer and chronic infectious disease, which need to induce cytotoxic T-cell responses via cross-presentation of the vaccine Ag by dendritic cells. The ISCOMATRIX adjuvant represents a unique adjuvant system that facilitates Ag delivery and presentation as well as immunomodulation to provide enhanced and accelerated immune responses. The immune responses generated are of broad specificity to the vaccine Ag, and include robust antibody responses of multiple subclasses as well as both CD4(+) and CD8(+) T-cell responses. Here we discuss our understanding of the mechanisms of action by which ISCOMATRIX adjuvant may facilitate these integrated immune responses and touch on insights gained through its clinical experience.