The tragic failure of gene therapy resulted in rolling back the research of gene-based medicine. Because of the poor delivery of gene-based medicines, such as antisense oligonucleotides, ribozyme, triplex, or gene both in vitro and in vivo, further development of gene-based medicines as therapeutic agents have stagnated. Although the delivery system plays a critical role in the overall efficacy of oligonucleotides, inappropriate target selection, improper evaluation methods and misinterpretation of results often caused the pessimistic view. Still, the decoding of the whole human genome has rekindled the enthusiastic development of delivery tools for gene-based medicine. We would like to focus on the newly developed delivery systems mainly for antisense oligonucleotides in this article. There are two ways to improve delivery efficacy of antisense oligonucleotides: One is the chemical modification of the antisense oligonucleotide backbone. The other way is by means of delivery vehicles, such as cationic liposomes, synthetic polymers, or non-viral vectors. We will review the current status of delivery vehicles both in vitro and in vivo. Delivery efficiency depends on the oligonucleotides chemistry, length, size, net charge, cell / tissue type and administration route. It is difficult to deduce a common rule that affects delivery efficiency. Some cells like keratinocytes rapidly internalize oligonucleotides without a delivery system, which is contrary to common belief. Although we cannot extensively cover all reports, we will summarize several experiments with delivery system in vitro and in vivo. We will then address the possible factors promoting the efficient delivery of oligonucleotides.