DNA is a complex macromolecule whose immunological properties vary with base sequences. As shown with synthetic oligonucleotides, potent immune stimulation results from six base motifs called CpG motifs or immunostimulatory sequences (ISS). These sequences center on an unmethylated CpG dinucleotide and occur much more commonly in bacterial DNA than mammalian DNA. As such, CpG motifs may function as a danger signal to stimulate B cell activation and cytokine production. In addition to CpG motifs, runs of deoxyguanosine (dG) residues in DNA can induce B cell activation and promote macrophage cytokine expression by adjacent CpG motifs. The array of these sequences may determine the overall immune activity of a DNA molecule and affect such processes as host defense against infection as well as the use of plasmids and synthetic oligonucleotides to treat disease.