Colloids from an aqueous suspension can cross the skin barrier only through hydrophilic pathways. Various colloids have a different ability to do this by penetrating narrow pores of fixed size in the skin, or the relevant nano-pores in barriers modelling the skin. Such ability is governed by colloid adaptability, which must be high enough to allow penetrant deformation to the size of a pore in such barrier: for a 100 nm colloid trespassing the skin this means at least 5-fold deformation/elongation. (Lipid) Bilayer vesicles are normally more adaptable than the comparably large (lipid coated) fluid droplets. One of the reasons for this, and an essential condition for achieving a high bilayer adaptability and pore penetration, is a high bilayer membrane elasticity. The other reason is the relaxation of changing colloid's volume-to-surface constraint during pore penetration; it stands to reason that such relaxation requires a concurrent, but only transient and local, bilayer permeabilisation. Both these phenomena are reflected in bilayer composition sensitivity, which implies non-linear pressure dependency of the apparent barrier penetrability, for example. Amphipats that acceptably weaken a membrane (surfactants, (co)solvents, such as certain alcohols, etc.) consequently facilitate controlled, local bilayer destabilisation and increase lipid bilayer flexibility. When used in the right quantity, such additives thus lower the energetic expense for elastic bilayer deformation, associated with pore penetration. Another prerequisite for aggregate transport through the skin is the colloid-induced opening of the originally very narrow ( approximately 0.4 nm) gaps between cells in the barrier to pores with diameter above 30 nm. Colloids incapable of enforcing such widening-and simultaneously of self-adapting to the size of 20-30 nm without destruction-are confined to the skin surface. All relatively compact colloids seem to fall in this latter category. This includes mixed lipid micelles, solid (nano)particles, nano-droplets, biphasic vesicles, etc. Such colloids, therefore, merely enter the skin through the rare wide gaps between groups of skin cells near the organ surface. Transdermal drug delivery systems based on corresponding drug formulations, therefore, rely on simple drug diffusion through the skin; the colloid then, at best, can modulate drug transport through the barrier. In contrast, the adaptability-and stability-optimised mixed lipid vesicles (Transfersomes, a trademark of IDEA AG) can trespass much narrower pathways between most cells in the skin; such highly adaptable colloids thus mediate drug transport through the skin. Sufficiently stable ultra-adaptable carriers, therefore, can ensure targeted drug delivery deep below the application site. This has already been shown in numerous preclinical tests and several phase I and phase II clinical studies. Drug delivery by means of highly adaptable drug carriers, moreover, allows highly efficient and well-tolerated drug targeting into the skin proper. Sustained drug release through the skin into systemic blood circulation is another field of ultradeformable drug carrier application.