Physiologically based oral absorption models are in silico tools primarily used to guide formulation development and project the clinical performance of formulation variants. This commentary briefly discusses additional oral absorption model applications, focusing on gut-level drug interactions. Gut-level drug interactions can involve drug degradation, metabolic enzymes, transporters, gastrointestinal motility modulators, acid-reducing agents, and food. The growth in publications reporting physiologically based oral absorption model utilization and successful pharmacokinetic prediction (e.g., after acid-reducing agents or food coadministration) indicate that oral absorption models have achieved a level of maturity within the industry particularly over the past 15 years. Provided appropriate data and model validation, oral absorption modeling/simulation may serve as a surrogate for clinical studies by providing both mechanistic and quantitative understanding of oral delivery considerations on pharmacokinetics.