Leading researchers review the activation of the mammalian immune system by bacterial DNA and its immunostimulatory sequences (ISS), and consider the applications of ISS in clinical medicine. The authors survey the latest findings concerning the receptor-recognition and signaling pathways triggered by ISS, the process of cell activation, and the potential vaccination strategies using ISS. Specific pharmaceutical applications discussed include infectious disease (Hepatitis B, HIV, and mycobacterial infections), allergy (asthma and conjunctivitis), cancer (lymphoma), and inflammation and autoimmunity (arthritis and colitis).