Sphingolipids had long been regarded as merely structural components of eukaryotic cellular membranes. Research has discovered sphingolipids to have crucial roles in cellular processes as bioactive molecules. Lately, there has also been an increased interest in sphingolipids and sphingolipid-metabolizing enzymes as mediators of microbial pathogenicity and as potential targets for the development of new therapeutics. This minireview will provide a comprehensive analysis of sphingolipid pathways in mammalian and microbial cells, highlighting their uniqueness and discussing their potential as therapeutic targets for microbial infections.