PURPOSE OF REVIEW: The identification of human Toll-like receptors has drastically changed our understanding of host-pathogen interactions. This review presents recent data on myeloid differentiation factor 2 (MD-2), a membrane-bound and soluble receptor for Gram-negative lipopolysaccharide, and its central role in the recognition of Gram-negative bacteria, phagocytosis, and Toll-like receptor 4 signalling. RECENT FINDINGS: Phagocytosis is a complex mechanism involving a variety of receptors and opsonins. The heterogeneity of phagocytic mechanisms allows the optimization of bacteria recognition, phagocytosis, and killing. Notably, Toll-like receptors were known to play a role in phagocytosis, both by modulating opsonins and phagocytosis receptors' expression and activity, and by contributing to bacterial recognition and presentation to host cells. Recent data provide additional insight into the function of Toll-like receptors and associated proteins. In addition to bacterial recognition and activation of inflammatory cascades, MD-2 has been recently shown to be an opsonin for Gram-negative bacteria and an acute-phase protein. These newly described characteristics directly link Gram-negative bacteria recognition, transduction of Toll-like receptor 4 inflammatory signalling, phagocytosis and bacterial clearance. SUMMARY: Recent progress in the understanding of Gram-negative bacteria recognition by host cells as well as physiologic functionality of MD-2 suggests that MD-2 is a critical compound in host response to pathogens and plays a central role in physiologic adaptation to various insults.