This chapter delves into transdermal approaches, including invasive (penetrating through stratum corneum) and non-invasive (drug diffusion) techniques, highlighting their underlying mechanism. This work provides a comparative understanding of minimally invasive drug delivery systems (MIDDS) with invasive as well as non-invasive techniques. The MIDDS technique enhances the penetration ability of macromolecules and hydrophilic substances, a challenge with non-invasive techniques. Further, a brief discussion on the potential challenges associated with invasive techniques is included. We have emphasised how the MIDDS can overcome the challenges by improving drug delivery efficiency and patient compliance with limited risk. Finally, this chapter provides insight into different MIDDS, such as microneedles, velocity-based devices, and laser- and radiofrequency-induced microporation techniques. In addition, it highlights newer aspects, such as a combination of microneedles with sonophoresis, iontophoresis, and vibratory actuation.