Liposomal bupivacaine (LB) has been the subject of a great deal of study, and some degree of controversy, since its development in the late 1990s. While some published studies are supportive of its efficacy, many others are not or demonstrate only marginal improvement in analgesia. This variable efficacy occurs in the face of markedly increased costs when compared with plain local anesthetics. In this education article, we trace the development of LB, summarize the important aspects of its pharmacology, and explore possible causes of its failure to fulfill the promise that the drug held when it was developed and approved. Finally, we discuss some aspects of perineural anatomy that might impact the potential of this drug to provide long-lasting analgesia.