Alveolar macrophages play an important role in defense against airborne pathogens and particles. These macrophages respond through both the adaptive and acquired immune responses, and through the activation of a multitude of signaling pathways. One major macrophage defense mechanism is respiratory burst, the production of reactive oxygen species (ROS). While the ROS produced may act directly in pathogen killing, they may also be involved as secondary signaling messengers. This review focuses on the activation of four main signaling pathways following the production of reactive oxygen species. These pathways include the nuclear factor kappa beta (NFkB), activating protein-1 (AP-1), mitogen-activating protein kinase (MAPK), and phosphotidyl inositol-3 kinase (PI3K) pathways. This review also briefly examines the role of ROS in DNA damage, in particular looking at the base excision repair pathway (BER), the main pathway involved in repair of oxidative DNA damage. This review highlights many of the studies in the field of ROS, signal transduction, and DNA damage; however, work still remains to further elucidate the role of ROS in disease.