The limited efficacy of current therapeutic approaches for a number of socially relevant human diseases has required the exploration of alternative and more effective therapeutic strategies. In the last three decades, nucleic acid based drugs (NABDs) have emerged as an attractive and novel alternative with great therapeutic potential. NABDs which include antisense oligonucleotides, decoys, aptamers, triple helix forming oligonucleotides, DNAzymes, Ribozymes and small interfering RNAs, have been shown to be able to efficiently counteract pathological gene expression in many different experimental systems. Despite their broad potential applicability, NABD use in the clinic is limited by the lack of optimal delivery systems. Due to their hydrophilic nature, NABDs cannot efficiently cross cellular membrane for which appropriate carriers are needed. Moreover, their instability in serum requires a proper protection to prevent a fast degradation which would invariably lead to the abrogation of any significant therapeutic effect. In this work we will review the strategies currently proposed to circumvent NABD delivery problems. Although the NABD delivery issue can and should be optimized to bring NABD closer to the clinic, the encouraging results displayed so far in experimental models fully justify further efforts both in terms of investments and scientific work.