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Gene-based therapeutics hold great promise for medical advancement and have been used to treat various human diseases with mixed success. However, their therapeutic application in vivo is limited due largely to several physiological barriers. The design of non-viral gene vectors with the ability to overcome delivery obstacles is currently under extensive investigation. These efforts have placed an emphasis on the development of multifunctional vectors able to execute multiple tasks to simultaneously overcome both extracellular and intracellular obstacles. However, the assembly of these different functionalities into a single system to create multifunctional gene vectors faces many conflicts that largely limit the safe and efficient application of lipoplexes and polyplexes in a systemic delivery. In the review, we have described the dilemmas inherent in the design of a viable, non-viral gene vector equipped with multiple functionalities. The strategies directed towards individual delivery barriers are first summarized, followed by a focus on the design of so-called smart multifunctional vectors with the capability to overcome the delivery difficulties of gene medicines, including the so-called the “polycation dilemma”, the “PEG dilemma” and the “package and release dilemma”.