There is growing evidence that several antibiotics exert their beneficial effect not only by inhibiting or killing bacterial pathogens but also by down-regulating pro-inflammatory mechanisms. This review aims to give an overview of the immunomodulatory properties of macrolide antibiotics in chronic rhinosinusitis and to present a treatment algorithm for managing the difficult CRS patient with long-term, low-dose macrolide antibiotics. The most prominent effect of macrolides noted in vitro is the inhibition of pro-inflammatory cytokines such as interleukin-8. This effect is probably secondary to inhibition of the activation of transcription factor NF-kappaB. As a result an attenuation of neutrophilic inflammation takes place. Moreover, macrolides inhibit bacterial virulence and biofilm formation. In vivo, a reduction of pro-inflammatory cytokines is evident in nasal lavage as well as a reduction in nasal secretions. The clinical effect is shown in less facial pain, less headache, less post nasal drip, fewer exacerbations of sinusitis and improved quality of life. The treatment should be targeted towards the non-atopic patients with bilateral disease whereas in unilateral disease, surgery is the first option. Macrolide resistant bacterial strains have to be monitored, but to date they have not been of clinical importance.