Absorption of drugs from the oral cavity into the mucosal tissues is typically a fast event. Dissolved drugs partition into the mucosal membranes and within minutes will reach equilibrium with drug in solution in the oral cavity. However, this does not always equate to rapid drug appearance in the systemic circulation. This has been attributed to slow partitioning out of the mucosal tissues and into the systemic circulation. Based on information from literature, physicochemical properties of asenapine, and clinical data, we conclude that for sublingually administered asenapine, the exposure is primarily a function of rapid partitioning into the mucosal membranes. This is followed by slow partitioning out of the mucosal tissues and into the systemic circulation, leading to a T (max) value of about 1 h. The bioavailability of asenapine at doses below the saturation solubility in the mouth does not change and is controlled primarily by mass transport equilibrium. At doses above the saturation solubility, the bioavailability becomes more dependent not only on the distribution equilibrium but also on contact time in the mouth because additional variables (e.g. dissolution rate of the drug) need to be accounted for. These explanations are consistent with oral cavity absorption models from the literature and can be used to accurately describe the clinical data for asenapine.