Human skin layers serve as a barrier between the body and the environment, by preventing water loss and blocking the entry of chemicals, allergens, and microbes. Recent data showed that skin lipids are vital ‘key players’ of several functions and mechanisms performing in the skin, such as, barrier function and microbiome composition. Abnormalities in lipid composition have been observed in inflammatory cutaneous diseases with a disrupted skin barrier. This review aims to demonstrate the fundamental role of keratinocytes, sebocytes, and microbiome-derived lipids in the maintenance of the skin barrier. Furthermore, it would reveal the correlation between altered skin lipids’ composition, microbiome, and the occurrence of certain dermatological disorders such as acne vulgaris, atopic dermatitis, psoriasis, and rosacea.