Gene therapy has been a promising strategy for treating numerous gene-associated human diseases by altering specific gene expressions in pathological cells. Application of nonviral gene delivery is hindered by various dilemmas encountered in systemic gene therapy. Therefore, solutions must be established to address the unique requirements of gene-based treatment of diseases. This review will particularly highlight the dilemmas in polycation-based gene therapy by systemic treatment. Several promising strategies, which are expected to overcome these challenges, will be briefly reviewed. This review will also explore the development of polycation-based gene delivery systems for clinical applications.