The presentation of lipid antigens by CD1 molecules follows precise rules imposed by the biochemical nature of lipids. The structures of CD1-lipid complexes are elucidating how T-cell receptors interact with hydrophobic antigens. The mechanism of lipid uptake and the pathways followed by lipids embedded in the cell membrane contribute to the efficient presentation of exogenous and self-lipids. Lipid presentation is further regulated by the trafficking route of CD1 proteins and their precise membrane localization within endosomal vesicles. Moreover, the generation of immunogenic lipids might require adequate processing, which occurs in the presence of lipid-binding proteins, including CD1e. Here, we review recent experimental evidence that has revealed new protagonists involved in generating immunogenic lipids and has indicated unexpected biological mechanisms contributing to immune recognition.