The purpose of the study was to investigate the molecular diffusion of drugs across porcine bronchial tissue. Using an in vitro flow-through diffusion system, a series of model compounds were tested. These included theophylline, caffeine, theobromine, enprofylline, salbutamol, ipratropium bromide, and trimethoprim. All drugs were assayed by HPLC in conjunction with UV/vis or MS/MS detection. The results indicated that the mean flux value of theophylline was higher than that of all the other drugs listed above. Within the log10P range from −2.21 (ipratropium bromide) to 1.364 (trimethoprim), a sigmoidal relationship was found to exist between the apparent permeability coefficients (Papp) and the octanol/water partition coefficients across the bronchial tissue. The diffusion of ipratropium bromide (Papp 1.6 × 10−8 cm/s) across bronchial tissue was similar to that of salbutamol (Papp 1.5 × 10−8 cm/s). The data obtained in this study indicate that although lipophilicity is a main determinant in the diffusion of drug compounds across bronchial tissue, the number and position of alkyl groups also reflect the ability of the latter to cross membrane barriers.