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The skin is refractive to most molecules, especially hydrophilic ones, despite the existence of trans-barrier pathways. It is essential to maintain this protective barrier even after breaching skin surface for purposes of transdermal drug delivery to cope with cutaneous microbiota. Mechanical abraders or local energy dischargers (porators) or else hard, sharp objects (perforators, micro-needles) can punch a limited number (˜ 102 cm− 2) of relatively wide (≥ 103 nm) openings in the skin barrier, which then lets transiently (˜ 1 day) small drug quantities (≤ 10 mg) and even large molecules (and pathogens?) pass. Microscopic (≥ 103 nm) ballistic droplets or particles also insert small drug amounts (˜ 1 mg) into the upper skin through the ≥ 106 cm2 pores they create. The latter “skin breaching” method is approved for use in humans, whereas the hard nano-sized (5 nm–10 μm) skin perforators are still in development for transdermal drug delivery. Alternatively, controlled and reliable drug delivery across skin barrier can be achieved with sufficiently deformable and stable nano-sized carriers. Such “soft” skin penetrators are typically composite colloids. As such they must obtain, or retain, their ability to act as drug carriers on, in, and ideally below skin barrier(s). If properly designed and applied, such self-regulating, ultra-adaptable, and stable hetero-aggregates can open spontaneously and carry drugs through ≤ 109 cm− 2 cutaneous pores in the primary skin barrier and minimise cutaneous drug clearance; this permits deep/targeted deposition and prolonged action of the carrier-transported drugs. Therapeutic products based on ultra-adaptable, self-regulating, nano-sized (˜ 102 nm) carriers are under development. The first one is already approved in Switzerland.