The ability to target gene expression with nucleic acid-based therapeutics including small interfering RNAs (siRNAs) has opened up novel treatment opportunities for genetic skin disorders. Although siRNAs have exquisite selectivity and potency, translation to the clinic has been hampered due to the lack of efficient delivery systems that allow penetration through the outer barrier of the skin, the stratum corneum, and uptake by the live cells of the dermis and epidermis. A number of physical and chemical methods have been used to deliver siRNA across the stratum corneum into the epidermis. Once in the tissue, the target cells must internalize the siRNA. “Self-delivery” siRNAs have been identified that obviate the need for transfection reagents and are widely used in vitro. However, cellular uptake of the most effective self-delivery siRNAs is still inefficient compared to siRNA complexed with transfection reagents. Other functionalities may enhance delivery, but screening large numbers of modifications for self-delivery properties is hindered by cumbersome RNA synthesis methods. The long-term goal of this project is to develop novel siRNA conjugates that will facilitate optimal delivery to the affected tissues and cells for treatment of genetic disorders, particularly those of the skin. Here, it is proposed to develop an efficient method for conjugating siRNAs to a library of small molecules. The proposed strategy takes advantage of standard thiol and amine chemistries, producing a stable, covalent crosslink between the siRNA and any molecule containing a primary amine. These conjugates will initially be screened using a keratinocyte cell line expressing a reporter gene. In preparation for translation to the clinic, lead inhibitors will be fully characterized and tested for their ability to specifically inhibit reporter and endogenous gene expression in vitro and in vivo.