Gene therapy is the manipulation of gene expression patterns in specific cells to treat genetic and pathological diseases. This manipulation is accomplished by the controlled introduction of exogenous nucleic acids into target cells. Given the size and negative charge of these biomacromolecules, the delivery process is driven by the carrier vector, of which the usage of viral vectors dominates. Taking into account the limitations of viral vectors, nonviral alternatives have gained significant attention due to their flexible design, low cytotoxicity and immunogenicity, and their gene delivery efficacy. That stated, the field of nonviral vectors has been dominated by research dedicated to overcoming barriers in gene transfer. Unfortunately, these traditional nonviral vectors have failed to completely overcome the barriers required for clinical translation and thus, have failed to match the delivery outcomes of viral vector. This has consequently encouraged the development of new, more radical approaches that have the potential for higher clinical translation. In this review, we discuss recent advances in vector technology and nucleic acid chemistry that have challenged the current understanding of nonviral systems. The diversity of these approaches highlights the numerous alternative avenues for overcoming innate and technical barriers associated with gene delivery.