The host lipid environment is a barrier to bacterial infection that comprises antimicrobial fatty acids and impermeable lipids that keep infectious agents from penetrating tissues. Bacterial and host lipids also signal to the immune system to regulate inflammation. Notably, bacterial lipids activate Toll-like receptors to initiate cytokine production, immune cell recruitment, and oxidative burst to control infection. Bacterial pathogens must adapt to the lipid environment, including bactericidal host fatty acids and inflammatory lipids, in ways that promote persistence in diverse tissues. Here, we discuss current advances in the understanding of Staphylococcus aureus lipid interactions that contribute to inflammation and innate immunity and consider the complex roles of host inflammatory lipids in driving immune defenses and antibacterial activity. In addition, we endeavor to introduce similar processes in other Gram-positive pathogens. These recent studies highlight the growing body of knowledge on the effects of lipid metabolism on host immunity and pathogenesis.