There has been considerable development in our knowledge about the mechanism of skin permeation. This has largely been brought about by the development of experimental techniques and increased computer technology, hardware and available software. The advanced computer technology and software have provided indications, relationships, at a molecular level, about routes of penetration and how the formulations can be formulated considering the effects of excipients and drugs on the barrier properties of skin layers. Available computer programs for molecular modeling have been used to calculate some molecular properties of the drug molecules such as surface area, partial charges etc. This publication reviews some of the mathematical models and techniques used some molecular descriptors and properties that have been constructed to predict and understand percutaneous penetration and transdermal delivery. The models are also useful for various enhancement strategies that can be used in dermal penetration and formulation development studies. If the appropriate biophysical techniques combined with the mathematical modeling and statistical analysis using computer, it can provide useful information for identifying the possible penetration processes when different classes of enhancers or excipients used in the formulation. Models are also useful for understanding which factors affect the penetration of molecules through skin and these factors/parameters can be used for the control of the penetration rate when effective transdermal delivery or therapy is required or targeted.