A wide range of actives target the skin for therapeutic or cosmetic purposes, and the stratum corneum (SC) is recognized as the major barrier to the percutaneous absorption of drugs and xenobiotics. I n vitro skin penetration is usually assessed in human or animal tissue. However, there are ethical and practical concerns associated with sourcing these materials. Hence, a reliable, robust, more accessible and efficient surrogate for evaluating permeation behavior would be beneficial. Niacinamide is the amide form of vitamin B3 and its dermal application has been shown to improve skin conditions including melanogenesis, atopic dermatitis, ultraviolet-induced DNA damage, acne and inflammation. Phenylethyl resorcinol is a tyrosinase inhibitor and has been used in the personal care industry as a novel skin lightening ingredient. Rational formulations of both actives are desirable. In this work, followed by characterization, both model actives were initially formulated into simple solutions based on their physicochemical properties. The permeation behavior was investigated using porcine and human skin, and a recently developed Parallel Artificial Membrane Permeation Assay (PAMPA) model under varying dose conditions. The feasibility of the Skin PAMPA model for prediction of human skin permeability was confirmed under clinically relevant dose conditions. Binary and ternary solvent systems were subsequently developed and evaluated using the three models under finite dose conditions. Skin penetration enhancement was evident for binary systems composed of propylene glycol and fatty acids. Finally, in vivo studies using confocal Raman spectroscopy (CRS) and tape stripping were conducted on human subjects. In vivo - in vitro correlation in skin permeation was observed for niacinamide. Overall PAMPA demonstrated its potential as a screening tool for simple topical formulations. The efficacy of topical formulations was also demonstrated to be enhanced by a rational selection of solvents; CRS is proposed as a suitable method for evaluation of in vivo permeation kinetic studies.