The skin has been employed as a delivery route for localized as well as systemic delivery of drugs. However, the Stratum corneum (SC) of the skin act as a main barrier for the percutaneous absorption of drug molecules. Therefore, in previous years numerous attempts have been made to overcome this barrier either by passive and/or active methods. The effectiveness of these techniques can be determined by studying the rate and extent of drug absorption into the different layers of skin. The study of drug-skin and/or drug-vesicle interaction is also critical for the safe and effective development of topical/transdermal drug delivery systems. But a comprehensive insight on the available models is still a miss. Therefore, the focus of this review article is to provide insight and up-to-date knowledge about the in-vitro (diffusions cells/type of skin employed), ex-vivo (tape-stripping and confocal laser scanning microscopy), in-vivo (microdialysis, dermal open flow microperfusion, in-vivo pharmacokinetic/dynamic assessment) and in-silico models (Quantitative structure-activity-relationship/Quantitative structure permeability relationships and physiologically based pharmacokinetic-pharmacodynamic approaches) for successful clinical translation of topical and transdermal delivery systems. The advantages and limitations of each model have also been critically discussed. We have also provided an insight into the integration of analytical techniques (ATR-FTIR, Raman confocal microscopy/spectroscopy, DSC, SEM/TEM, and P³¹ NMR) with these models for the assessment of the interaction of drug-vesicle and/or drug with skin layers. Hence, it is suggested to use in-vitro methods together with ex-vivo and/or in-vivo studies for swifter lab to clinical translations of the novel developed topical and transdermal drug delivery systems. Furthermore, the tandem use of QSPR and full-body PBPKPD modeling can further expedite the development process.