Transdermal delivery serves as non-invasive and effortless terminable means for systemic as well as topical drug delivery and finds itself as an option to conventional delivery route. Significant impervious nature of skin is the greatest hurdle for successful delivery of drug molecules to the deeper layers of skin for systemic absorption. Many approaches have been carried out for delivery of a medicament across skin barrier to enhance the efficacy. Among them lipid-based colloidal carriers have gained a unique position for transdermal delivery of drugs and bioactives owing to the presence of epidermal lipids as the chief component within the penetration barrier in high amount. Skin-carrier interaction involves attachment of these carriers to skin with a view to permit exchange of lipid between the outermost layers of the stratum corneum. Based on extensive literature search, although numerous reviews are available on lipid-based systems, but none of them relates exclusively to their transdermal uptake and toxicity. This review specifically focuses on the hurdles of transdermal drug delivery, role of lipid vehicular systems in transdermal drug delivery, uptake pathways, sequential uptake mechanism and cytotoxicity issues of lipid-based carriers which although considered safe, are not completely free from toxicity.