Scavenger receptor class B, type I (SR-BI) is a crucial molecule in lipid metabolism, since the interaction of high-density lipoproteins (HDLs) with SR-BI is involved in reverse cholesterol transport and cholesterol efflux. Recent findings also underscore a critical role of SR-BI in antimicrobial and immune responses. SR-BI is not only highly expressed in liver and steroidogenic glands, but also in endothelial cells, macrophages and dendritic cells. SR-BI mainly mediates anti-inflammatory responses, which may be altered by dysfunctional HDLs produced in several diseases. Moreover, SR-BI has been involved in the capture and cross-presentation of antigens from viruses, bacteria and parasites. It thus works as a pattern-recognition receptor that interacts with both damage-associated molecular patterns and pathogen-associated molecular patterns. These new findings in the microbiology and immunology fields present SR-BI as an unexplored therapeutic target that warrants further basic and applied research.