Streptococcus pneumoniae is a global cause of morbidity and mortality. During pulmonary S. pneumoniae infection, a unique and versatile subset of T lymphocytes called invariant natural killer T (iNKT) cells plays a critical role in host protection of mice. The microbial antigen in S. pneumoniae is an abundant, glucosylated diacylglycerol molecule containing vaccenic acid (18:1n7). Antigenic activity of this molecule is lost when vaccenic acid is substituted, even with closely related fatty acids such as oleic acid (18:1n9). In order to investigate the possible contribution of self-lipids as opposed to microbial lipids during Streptococcus infection, we generated an S. pneumoniae mutant with an altered fatty acid biosynthesis that is unable to produce the previously identified iNKT cell antigen. This mutant is highly dependent upon exogenous C18 fatty acids for its growth, and shows a strongly reduced ability to stimulate protective iNKT cell responses in vitro and in vivo. Mice infected with this mutant had an elevated bacterial burden and lower survival rate when compared to mice infected with the wild-type strain, demonstrating that foreign antigen recognition is the dominant pathway for iNKT cell stimulation in mice. Interestingly, wild-type bacteria rapidly turn off expression of genes involved in fatty acid biosynthesis in the presence of abundant host fatty acids suggesting a mechanism to save metabolic energy. By manipulating serum free fatty acid levels in the host, we show that the switch from synthesis of vaccenic acid to incorporation of exogenous fatty acids from the host also provides an important immune evasion strategy for S. pneumoniae to prevent its recognition by iNKT cells.