<p>The transappendageal (follicular) pathway plays a significant role in percutaneous absorption. Sebaceous glands, as part of the pilosebaceous unit, may act as reservoirs for various compounds, influencing drug retention and release. Drug targeting using the transappendageal pathway was identified as a possible mechanism both locally and systemically. Sebum may influence the permeability of stratum corneum (SC) in skin through altered barrier function. The difficulty of isolating the sebaceous gland has led to little direct data on its effect on percutaneous absorption. Advanced imaging modalities now allow direct visualization of sebum-drug interactions at submicron resolution. Emerging techniques like confocal Raman microscopy and dermal microdialysis now enable real-time, gland-specific permeation analysis, addressing translational gaps between rodent and human models. This review critically evaluates how sebum composition, gland density and follicular physiology influence permeation, synthesising evidence from rodent, porcine and human studies and highlighting formulation variables, including particle size and ethanol-mediated lipid fluidisation, that can be leveraged for sebaceous targeting. Deciphering sebum-mediated transport is indispensable for designing safer, more effective topical and transdermal medicines; emerging analytical platforms finally offer the resolution required to translate transappendageal delivery concepts into patient-tailored therapies.</p>