When bodily surface barriers have been breached, invading microorganisms are confronted by the innate immune system [1]. The first step in mounting a protective response is the rapid activation of an acute inflammatory response characterized by the migration and accumulation of immune cells at the site of invasion. As a primary defense against microbial infections, professional phagocytic cells such as macrophages will attempt to engulf and dispose of the invading microorganisms and their products. The recognition by effector cells of the innate immune system initiates signaling cascades, resulting in phagocytosis, secretion of microbicidal compounds and production of proinflammatory mediators. These early events culminate in the activation of adaptive immune responses; therefore, if launched early and effectively, innate immune responses limit the establishment of infectious foci and curb the severity of infections. However, it becomes more and more evident that microbial pathogens have developed very efficient strategies to circumvent and misguide host defenses, and therefore, their presence in the host results either in their elimination or in infection. Because of the critical role the innate immune system has in controlling microbial burden during the early stages of infection, the mechanisms employed by invading pathogens to thwart host immune defenses have attracted increasing interest. Here we synopsize some of the strategies exploited by two ubiquitous yet important human pathogens, the fungal species Candida albicans and the bacterial species Staphylococcus aureus [2, 3]. In addition to possessing an array of virulence factors, these diverse species share many pathogenic characteristics, including the ability to form biofilms on host and abiotic surfaces, rapid development of antimicrobial resistance, and the ability to alter their transcriptome in response to stresses inflicted upon them by host immune cells. Importantly, although C. albicans and S. aureus are commensal species commonly colonizing various niches in the human host, they are the most frequent combination of organisms isolated from polymicrobial infections [4].