Macrolide antimicrobials have stimulated worldwide interest owing to their therapeutic effects in various inflammatory, apparently non infectious, diseases. Abundant data are now available on their interactions with host cell (specially phagocyte) functions. Modulation of oxidant production by neutrophils and of pro-inflammatory cytokine synthesis and release by leukocytes are the two main effects observed in vitro. However, despite an extensive literature, many questions remain, such as the cellular/microbial target(s) of macrolide action, the critical chemical structure(s), and the usefulness of combining antimicrobial and anti-inflammatory properties, which during long-term treatment, could lead to increased microbial resistance. Also, because of the multiplicity of macrolide effects on different cell subsets, a unifying hypothesis for macrolide interactions with host cells is lacking. Novel analytical methods will certainly lead to new macrolide-based therapeutic strategies in cancer and inflammation.