Human cytochromes P450 (CYPs) are membrane-anchored enzymes involved in biotransformation of many marketed drugs. We constructed atomic models of six human CYPs (CYP1A2, 2A6, 2C9, 2D6, 2E1, and 3A4) anchored to a lipid bilayer to investigate the positions and orientations of CYPs on a membrane. We equilibrated the models by molecular dynamics simulations on a 100+ ns time scale. Catalytic domains of all studied CYPs were found to be partially immersed in the lipid bilayer, whereas the N-terminal part and F'/G' loop are deeply immersed The proximal side of the enzyme faces the cytosol, whereas the distal side, where openings of substrate access and product release channels to the active site are primarily located, points toward the lipid bilayer. Access channels with openings in the vicinity of the B/C and FIG loops are typically positioned below the lipid head groups, whereas the solvent channel points toward the membrane water interface. We found that the access channel opening positions match the preferred substrate positions, whereas the product release channel exit positions correspond closely with the positions of the products This may indicate that membrane anchored CYPs have evolutionarily adapted to facilitate uptake of nonpolar substrates from the membrane and uptake/release of polar substrates or products from/to the membrane-water interface.