In this issue of the Journal, Bawolak et al.1 focus their studies on a mechanism that provides a provocative insight into the complexity of systems that organize the intracellular environment. This mechanism may also serve to describe the effects produced by agents that are applied in high concentrations to the outer membrane of the cell… in this case, local anesthetics. As the authors note, aside from their block of sodium channels in excitable membranes, local anesthetics are known to have many “off target” effects. The authors discuss a mechanism that reflects upon the effect of local anesthetics, specifically procaine and lidocaine, in forming intracellular vacuoles and the role of a specific enzyme in vacuolar (V)–ATPase in producing this phenomena. I comment on this paper from the perspective of the potential significance of this vacuolar mechanism, not only from the perspective of the smooth muscle cell that they employ but from the point of view of the potential effects of this mechanism on issues resulting from the effects of local anesthetics on nerves, the typical intended target systems for which these agents are most commonly employed. The clinically relevant phenomenon of “conduction block” produced by cocaine was revealed in the late 19th century by the topical delivery of that agent to tissues such as the cornea or by delivery directly to the peripheral nerve or spinal cord using the hypodermic needle and syringe. Recognizing the limitations and side effects posed by the drug, early pharmaceutical chemistry led to the synthesis of a variety of analogues with an early appreciation that distinguishing elements of the structure activity relationship were the amino ester and amino amide linkages which form a weakly basic structure.2