For centuries, opioids have been implicated in increasing susceptibility to infection, reducing bacterial clearance, and increasing bacterial dissemination. Macrophages as key cells of innate immunity play an essential role in pathogen clearance and antigen presentation. Macrophage phagocytosis is a key mechanism responsible for host defense against bacterial pathogens. Although it is known that opioid addicts are prone to both bacterial and viral infections, the molecular and cellular mechanisms underlying these processes remain to be elucidated. Therefore the goal of this research was to investigate mechanisms of decreased bacterial clearance as a contributing factor in the increased susceptibility to infection in opiate drug abusers. To this end, first set of studies examined the role of morphine on inhibition of key mechanisms involved in Fc-gamma receptor mediated phagocytosis. It was demonstrated that morphine inhibits phagocytosis by inhibiting actin polymerization through a cAMP, PKA and MAPK dependant pathways. By superactivation of adenylyl cyclase morphine increases intracellular cAMP leading to inhibition of actin polymerization. Furthermore, morphine by inhibiting p38 MAPK and ERK 1/2 MAPK causes inhibition of actin polymerization and phagocytosis. By modulating TLR4 receptor function morphine was also able to increase macrophage phagocytosis, indicating that morphine might have a differential effect on internalization of Gram-positive, versus Gram-negative pathogens. These effects were mediated through a MyD88 and p38 MAPK dependant pathways leading to changes in actin polymerization and phagocytosis. In addition to macrophage's ability to internalize pathogens, elimination of internalized pathogen is essential for effective bacterial clearance. We therefore set out to investigate morphine's modulation of macrophage bactericidal mechanisms. We note that morphine inhibits bacterial killing by inhibiting essential mechanisms involved in this process such as formation of reactive oxygen intermediates, reactive nitrogen intermediates, as well as phago-lysosomal fusion. Morphine by inhibiting these essential mechanisms impedes eradication of bacterial infections and leads to detrimental consequences for the host. These series of studies have extended our knowledge in an underrepresented yet clinically significant field of study, however many questions still remain to be addressed and it is crucial to investigate the answers given the prevalence of morphine use today.