The stratum corneum (SC) (i.e., the outermost layer of human skin) is a complex and paradoxical tissue composed of corneocytes and a matrix of intercellular lipids playing an essential role as the skin's protective barrier. The first paradox of SC is its dual nature. It is composed of nondividing (dead) cells embedded in a metabolically active (live) environment whose function is to protect the epidermis and to maintain its integrity. In order to do so, the SC uses various strategies, including enzymatic reactions, colonization by bacterial flora, immune signaling, antimicrobial lipids and peptides, low pH, antioxidants, and natural moisturizing factor(s). The second paradox is that although its biological function is essentially that of a physicochemical barrier, cosmetologists and pharmacists are actively exploring paths for penetration through the SC to allow passage of active molecules and their penetration into the skin. Various pathways of penetration and physicochemical factors facilitating this penetration into the dermis and/or the epidermis have been defined, but the exact mechanisms of penetration of cosmetic ingredients remain elusive. For cosmetologists and pharmacists, the SC represents a major focus of interest whether for basic research or the development of novel topical approaches taking into account the fascinating properties of this complex tissue.