Transdermal drug delivery across the highly lipophilic uppermost layer of the skin, the stratum corneum, is highly challenging. Importantly, permeation of hydrophilic small or high molecular weight and charged compounds into the systemic circulation is limited. To successfully deliver hydrophilic drugs, and macromolecular agents of interest, including peptides, DNA and small interfering RNA, many research groups and pharmaceutical companies worldwide are focusing on the use of microporation-based enhancing techniques. These techniques include the use of laser, thermal ablation, electroporation, radiofrequency, ultrasound, high-pressure jets, and microneedle technology. All of these share the common goal of enhancing the permeability of a biological membrane through the creation of transient aqueous transport pathways of micron dimensions across that membrane. Once created, these micropores are orders of magnitude larger than molecular dimensions, and therefore should readily permit the transport of hydrophilic macromolecules. Additionally, microporation devices also enable minimally invasive sampling and monitoring of biological fluids. This Chapter deals with the innovations relating to microporation based methods and devices for transdermal drug delivery and minimally invasive monitoring.