Liposomes are emerging cargoes for bioactive delivery owing to their widely accepted biocompatible and biodegradable nature. It is always a challenge to control the release of payload for effective delivery to the site of interest. Over the couple of decennia, mathematical modeling of release process is a need of time whether the drug remains in the circulation or reaches at the target site. For establishing a better in vitro – in vivo correlation, release kinetics models viz. Peppas, Higuchi, Weibull, Zero Order and First order including mechanistic models like All-or-None, Toroidal, and Biomembrane models etc. are continuously exploited to predict drug release profile. Most of these models rely on the diffusion equations based on the composition of liposomes and conditions of release. Here, we summarized the crucial reports exploring these models and associated interventions to know the underlying physicochemical release phenomenon. Such mathematical model fitting can be a promising approach to deduce release/delivery process to help in designing the safe and efficacious (“Smart”) liposomes.