The advent of high-throughput screening (HTS) has enabled successful unbiased drug-discovery and fostered the development of novel therapies. Arguably the most fruitful targets in HTS platforms have been membrane proteins that comprise 22% of the proteins encoded by the genome and are targeted by 60% of the approved drugs available today. Almost half of these drugs are directed at the rhodopsin-like class I G protein-coupled receptor (GPCR) superfamily. Many of these receptors have underlying roles in a myriad of diseases, including cancer, heart disease, diabetes, and mental illness. Therefore, membrane proteins represent a goldmine of targets that must be screened to fully exploit their rich therapeutic potential. HTS platforms for plasma membrane receptors have had success due to reliable cell-based systems for monitoring the diversity of downstream messenger pathways, such as cAMP signaling, calcium mobilization, and Rho GTPase activation. However, in most cases, these assays are highly idiosyncratic and consequently require the development of specialized protocols. HTS becomes particularly challenging for those receptors that are of great therapeutic interest but have non-canonical signaling or remain uncharacterized. Thus, plasma membrane trafficking is the single universal feature of membrane receptor protein regulation. The reasons why HTS trafficking screens are not more often utilized include a lack of reagent universality, high costs of imaging equipment, and confounding background fluorescence that in many instances requires sophisticated deconvolution algorithms to identify subpopulations of membrane proteins. Our solution relies upon a new class of assay able to monitor in real-time membrane protein traffickin g by the simple addition of the corresponding drug without the need for reagent washes or highly automated equipment. We validated our assay with GPCRs of well-known pharmacology, therefore confirming its utility for screening and identifying pharmacological properties of novel drugs for a wide range of diseases. Additionally, these assays can be applied to identify pharmacological novel drugs for COVID-19.