In recent years, the position of the innate immune system in regulating nearly all immune responses has become well established. A central tenet in understanding the function of the innate immune system is the concept that it is triggered by pattern recognition receptors (PRRs), which bind microbial structures that are not present in host tissues. Examples of PRRs that have become well accepted are the lipopolysaccharide (LPS) receptors, such as CD14, and mannose-binding protein. Likewise, complement proteins have a primitive ability to bind and be activated by microbial structures. Viral RNAs are thought to adopt certain structural conformations that are bound by PRRs and lead to the activation of the double-stranded-RNA-dependent protein kinase PKR (Kumar et al. 1997). This mechanism is thought to be responsible for immune activation by the polynucleotide (rI, rC) (Talmadge et al. 1985; Wiltrout et al. 1985). Evidence that bacterial DNA (bDNA) may also possess some structural feature that activates innate immune defenses was first provided by Tokunaga et al. who reported its Surprising antitumor activity and ability to activate natural killer (NK) cells (Tokunaga et al. 1984; Yamamoto et al. 1988). Further studies by these investigators led to the proposal that this immune-stimulatory activity of bDNA resided in certain self-complimentary, palindromic sequences that contained CpG dinucleotides (Kuramoto et al. 1992). Interestingly, methylation of the CpGs was initially thought to have no influence on the immune stimulatory activities of DNA (Kuramoto et al. 1992).