Skin presents itself as an attractive portal for delivery of therapeutic molecules for local and systemic effects. A number of needle-free transdermal drug delivery applications have been developed for breaching the skin barrier and deliver pharmaceutics. Despite decades of research and usage history, several of these applications suffer from low acceptance due to limitations in potency and safety. As part of this study, we demonstrate approaches for increasing potency and safety for two of these applications, namely liquid jet injectors and chemical permeation enhancers. Mechanistic understanding of interactions between skin and conventional liquid jet injector was used to design a novel pulsed-microjet injector. The high velocity nu ＞ 100 m/s) of microjets was coupled with small jet diameters 50-100 mum) and extremely small volumes 2-15 nanoliters) to limit penetration depth inside skin. Microjets showed superficial skin penetration -200 mum) and minimal tissue damage, thus increasing safety compared to conventional injectors. The pulsed-microjet showed high insulin bioavailability in rat model. Combinatorial high throughput screening of binary ternary and quaternary chemical formulations was conducted using In vitro Skin Impedance Guided High Throughput INSIGHT) screening for discovering formulations with high potency. Ternary formulations represented the peak in potency i.e. highest average skin permeation enhancement amongst all orders and highest percentage of potent formulations. Potency screening of ternary formulations via INSIGHT was then coupled with cytotoxicity and adjuvanticity screening for discovery of safe formulations for needle-free transcutaneous immunization. A leading ternary formulation BDC [1%] PEG [0.5%] SOS [0.5%]) exhibited over 40-fold enhancement in IgG titers against ovalbumin, a model macromolecular vaccine, in mouse model. Finally, the safety of chemical enhancers as microbicides was improved via a combinatorial screening of binary formulations. Lead formulations showed lower toxicity towards epidermal keratinocytes, with LC50 values up to 3.5-fold higher than their component surfactants, while maintaining antibacterial efficacy against B. thailendensis , a model pathogen for melioidosis causing B. pseudomallei .