Macrolides, an old class of antibiotics, have attracted intense interest in recent years because of their diverse non-antibiotic properties. Among these properties, their immunomodulating effects were most extensively examined. In this review, their broad range of effects on the immune system as shown by various in-vitro, ex-vivo, and in-vivo experiments and clinical studies were discussed. It is now evident that various macrolides can modulate the innate immune system, with greater effects from 14- and 15-membered than the 16-membered derivatives. Although results from in-vitro studies appear to depend on the use of individual drugs and experimental conditions, they provide clues to the mechanisms of modulating different pathways of the immune system. On the other hand, animal and clinical studies, which summarize the effects of individual pathways, concluded that many macrolides are useful in a wide variety of clinical situations, from treatment of inflammatory lung diseases to application in transplantation. As for adaptive immunity, limited data were available but attenuation by macrolides was also reported in preliminary studies. Owing to their diverse effects on the immune system and inconclusive results from different in-vitro studies, the mechanism of their immunomodulation is not yet fully understood and correlation of effects with chemical structures is not conclusive at the moment. It may be more valuable for future studies to concentrate on the genetic basis for mechanisms on one hand, and additional areas of clinical applications on the other.