Early drug development gets a boost with cell-based in vitro models for drug permeation. These cost-effective tools track absorption rates and mechanisms, using immortalized epithelial cells that mimic various barriers (gut, lung, skin, etc.). This review explores key models and the intriguing challenge of bridging the gap between in vitro and real-world human absorption. Refining these models holds the key to optimizing drug discovery and bringing promising candidates to fruition.