In a challenging and insightful commentary, Sanes and Lichtman (1999) courageously point out in print what has often been discussed at recent meetings: LTP seems to have lost its usefulness as a paradigm for studying synaptic plasticity, much less learning and memory. The authors then offer two broad explanations for the current profusion (and confusion) of potential molecular mechanisms for LTP. The first is the simple suggestion that “Many molecules are required to mediate the process.” The second is that a variety of historical, experimental, and biological “factors have thwarted attempts to pinpoint a minimal cadre of essential molecules among a larger group of candidates.” Sanes and Lichtman favor this second, less optimistic explanation. I will argue that the truth lies somewhere in between. Sanes and Lichtman suggest that one reason we have a clear molecular explanation for, say, the action potential but not for LTP is that “the molecular biologists and biochemists studying action potentials knew what they were trying to explain.” In contrast, they correctly point out that it has “remained a challenge to supply a clear definition, description or function” for LTP. I agree that the inability to measure with a microelectrode alone the subtle mechanistic differences between one form of long-lasting synaptic potentiation and another has prevented a clear definition of LTP. The problem is magnified because the Nature of modern Science of the Cell biology of the Neuron has been to equate function with what is measured by a microelectrode. Thus, the trend has been to accept almost any manipulation that alters the tetanus-induced increase in EPSP slope as a legitimate functional study of LTP. It seems evident that a new paradigm is needed. In fact, many investigators have been quietly forging new ways of investigating synaptic regulation in the CNS, despite the frustration of having their work often relegated to non-functional status. In theory, there are a finite number of ways to change the strength of synaptic transmission. For example, the probability that a presynaptic action potential causes release of a vesicle of transmitter can be altered. An able group of molecular biologists and biochemists have made great strides in understanding this facet of synaptic regulation by investigating the molecular mechanisms of vesicular transmitter release. These studies, starting with descriptions of the proteins in synaptic vesicles (Reichardt and Kelly 1983) and interacting proteins in the plasma membrane (Bennett and Scheller 1994), have lead inevitably to exciting insights into the mechanisms of controlled synaptic vesicle fusion (Sutton et al. 1998; Chen et al. 1999). The next step will be to clarify the sites of regulation by calcium and by protein phosphorylation (Bennett 1997; Bajjalieh 1999). Another way that synaptic strength can be altered is to change the magnitude of the current-through-activated postsynaptic glutamate receptors. Here again, molecular biologists and biochemists have defined COMMENTARY