Background/Objectives: Predicting whether a compound is subject to active transport is crucial in drug development. We propose a simple threshold for passive membrane permeability (P_m), derived from the cell’s energy limitation, to identify compounds unlikely to be actively effluxed. Results: By considering fundamental cellular energy constraints, our approach provides a mechanistic rationale for why compounds with very high passive permeability in combination with low applied concentration will not undergo active efflux. This moves beyond the empirical observation (such as in previous systems that associate fast-permeating, poorly soluble compounds with low transporter activity) by grounding the prediction in the cell’s energetic limitations. For MDCK (Madin–Darby canine kidney) cells, this threshold—normalized to the applied compound concentration (C_ext)—was determined to be P_m×C_ext = 10^−1.7 cm/s×µM. Methods: To derive this threshold, we conducted an extensive analysis of literature-reported efflux ratios (ERs) in MDCKII cells overexpressing efflux transporters (MDR1, BCRP, MRP2; 294 datapoints across 136 unique compounds). Concentration-dependent measurements for Amprenavir, Eletriptan, Loperamide, and Quinidine—chosen because these borderline compounds exhibited the highest P_m×C_ext while still being actively effluxed—enabled the most accurate determination of the threshold. Literature ER values were re-evaluated through the experimental determination of reliable P_m values, as well as newly measured ER values with MDCK efflux assays. Conclusions: The results of these assays and the re-evaluation allowed us to reclassify all but three outliers (compounds with ER > 2.5 and log(P_m×C_ext) > −1.7). In contrast, more than 60% of the compounds analyzed without significant ER values (123 compounds) fell above the threshold, in strong agreement with our theory of an energy limitation to active transport. This permeability threshold thus provides a simple and broadly applicable criterion to identify compounds for which active efflux is energetically not feasible and may serve as a practical tool for early drug discovery and optimization, pending further validation in practical applications.