In addition to their physiological roles, these peptides and their derivatives have been proposed as future antimicrobial therapeutics, relatively unaffected by the development of sustained microbial resistance. Although initially characterised as directly microbicidal agents, it is now clear that many CHDP also have multiple functions as modulators of inflammation and immunity, with emerging roles in diseases affecting multiple organs including the lung, skin and gastrointestinal tract. Human clinical trials using analogues of CHDP modified to maximise direct microbicidal function have achieved only moderate efficacy, perhaps due to failure to recognise the importance of the immunomodulatory functions of the native peptides. Interestingly, studies using non-microbicidal analogues of naturally-occurring CHDP that retained other bioactive functions, have demonstrated effective host defence augmentation in mice. These studies raise questions about the relative roles of microbicidal and immunomodulatory properties of naturally-occurring CHDP in infections. These studies demonstrate a critical, nonredundant role for endogenous cathelicidin in host defence against lung infection and the therapeutic potential of the unmodified peptides, but the mechanisms by which pulmonary host defence is enhanced in vivo remains unclear. Although generally presented as being primarily a consequence of direct microbicidal activity, this is not fully consistent with in vivo concentrations and microbicidal properties in a physiological environment. However, the extent to which any of the plethora of immunomodulatory properties ascribed to cathelicidins play a significant role during infection has never been demonstrated in vivo. Understanding the critical modulatory roles of native CHDP and how these contribute to innate host defence against infection, may prove to be vital in development of specific pathogen-targeted analogues of these peptides for therapeutic use. Respiratory diseases are among the most common causes of morbidity and account for 1 in 5 deaths in the UK. A third of mortalities are due to acute respiratory infections, influenza or pneumonia and pathogens resistant to conventional therapeutics represent an increasing clinical challenge. Pseudomonas aeruginosa is the primary cause of nosocomial pulmonary infections and pulmonary colonisation with this pathogen is considered to be responsible for the fatal deterioration of lung function in patients with cystic fibrosis. This opportunistic pathogen is difficult to treat because of its widespread resistance to multiple antibiotics, with the limited number of effective antimicrobial treatments reduced further by the emergence of carbapenem-and polymyxin-B resistant isolates. A greater understanding of the natural host defence mechanisms involved in pulmonary defence against this organism is required in order to develop novel therapeutic approaches.