Understanding how neuronal activity changes and detecting such changes in both normal and disease conditions is of fundamental importance to the field of neuroscience. Neuronal activity plays important roles in the formation and function of both synapses and circuits, and dysregulation of these processes has been linked to a number of debilitating diseases such as autism, schizophrenia, and epilepsy. Despite advances in our understanding of synapse biology and in how it is altered in disease, the development of therapeutics for these diseases has not advanced apace. Many neuronal activity assays have been developed over the years using a variety of platforms and approaches, but major limitations persist. Current assays, such as fluorescence indicators are not designed to monitor neuronal activity over a long time, they are typically low-throughput or lack sensitivity. These are major barriers to the development of new therapies, as drug screening needs to be both high-throughput to screen through libraries of compounds, and longitudinal to detect any effects that may emerge after continued application of the drug. This review will cover existing assays for measuring neuronal activity and highlight a live-cell assay recently developed. This assay can be performed with easily accessible lab equipment, is both scalable and longitudinal, and can be combined with most other established methods.