During the past decades, encouraging progress has been made in the prevention of surgical site infections (SSI). However, as SSI still occur today, strategic prevention measures such as standardized skin antisepsis must be implemented and rigorously promoted. Recent discoveries in skin physiology necessitate the development of novel antiseptic agents and procedures in order to ameliorate their efficacy. In particular, alternate target structures in the skin need to be taken into consideration for the development of the next generation of antiseptics. Recent investigations have shown that a high number of microorganisms are located within and in the close vicinity of the hair follicles. This suggests that these structures are an important reservoir of bacterial growth and activity in human skin. To date, it has not been fully elucidated to what extent conventional liquid antiseptics sufficiently target the hair follicle-related microbial population. Modern technologies such as tissue-tolerable plasma (TTP) have been tested for their potential antiseptic efficiency by reducing the bacterial load in the skin and in the hair follicles. First experiments using liposomes to deliver antiseptics into the hair follicles have been evaluated for their potential clinical application. The present review evaluates these two innovative methods for their efficacy and applicability in preoperative skin antiseptics.