Resistance to antimicrobial agents and the limited development of novel agents are threatening to worsen the burden of infections that are already a leading cause of morbidity and mortality. This has increased interest in the development of novel strategies such as selective modulation of our natural immune defences. Innate immunity is a complex, evolutionarily conserved, multi-facetted response to defeating infection that is naturally stimulated by pathogenic organisms through pattern recognition receptors on host cells. It is amplifiable and broad spectrum but if overstimulated can lead to the potential for harmful inflammatory responses. A broad variety of therapies are already available or increasingly under development, to stimulate protective innate immunity without overtly stimulating harmful inflammation or even suppressing such damaging pro-inflammatory responses.