The application of gene and RNAi-based therapies to the central nervous system (CNS), for neurological and neurodegenerative disease, offers immense potential. The issue of delivery to the target site remains the single greatest barrier to achieving this. There are challenges to gene and siRNA (small interfering RNA) delivery which are specific to the CNS, including the post-mitotic nature of neurons, their resistance to transfection and the blood-brain barrier. Viral vectors are highly efficient and have been used extensively in pre-clinical studies for CNS diseases. However, non-viral delivery offers an exciting alternative. In this review, we will discuss the extracellular and intracellular barriers to gene and siRNA delivery in the CNS. Our focus will be directed towards various non-viral strategies used to overcome these barriers. In this regard, we describe selected non-viral vectors and categorise them according to the barriers that they overcome by their formulation and targeting strategies. Some of the difficulties associated with non-viral vectors such as toxicity, large-scale manufacture and route of administration are discussed. We provide examples of optimised formulation approaches and discuss regulatory hurdles to clinical validation. Finally, we outline the components of an "ideal" formulation, based on a critical analysis of the approaches highlighted throughout the review. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.