The gene therapy concept was developed more than forty years ago. Edward Tatum in a historic lecture affirmed: “We can anticipate that viruses will be used effectively for man's benefit, in theoretical studies concerning somatic cell genetics and possibly in genetic therapy... We even can be somewhat optimistic about the long-range possibility of therapy based on the isolation or design, synthesis, and introduction of new genes into defective cells of particular organs”. Two years later Marshall Niremberg predicted that: “in 25 years it would be possible to program the cells with synthetic messages”, but called to attention that “it should be postponed until having the sufficient wisdom to use this knowledge for the benefit of mankind”. Initial efforts to construct vectors were achieved by Rogers and Pfudere in 1968. However, it was not until 1990 that the first gene therapy clinical trial was carried-out in a patient with adenosine deaminase (ADA) deficiency (Friedmann, 1992). Within the last several years, significant advances have been attained in therapies for cancer, AIDS, Parkinson’s disease, Xlinked severe combined immunedeficiency (X-SCID), hemophilias, cystic fibrosis, Leber's congenital amaurosi, and β-thalassemia, among others. Nonetheless, an adolescent patient suffering from a urea cycle defect died of an anaphylactic reaction a few hours after being injected with an adenoviral vector. Soon after, five children participating in a clinical trial to correct a X-SCID developed a leukemia-like condition due to the activation of an oncogene (Edelstein, 2007). Recently, the tragic death of a volunteer in an clinical trial for rheumatoid arthritis using an adenoassociated virus vector was initially associated to a side effect of the vector (Williams, 2007). However, further studies showed that this was caused by an infection with Histoplasma capsulatum, which was produced by an immunosuppression condition induced for a simultaneous systemic anti-TNF-alpha therapy in the form of the drug adalimumab (Williams, 2007). All these failures halted the progress of gene therapy and seriously questioned the efficacy of the procedure. It also prompted the need for more basic studies on the immunogenic aspects and how to make safer, and more efficient vectors. During the last 35 years a long list of viral and non-viral vectors have been developed to design a vector that allows gene delivery to specific cell types, has a high gene transfer efficiency, produces therapeutic levels of gene expression during long-term periods, and minimizes the generation of side effects (Verma & Weitzman, 2005). Although the field has made great strides in producing an ideal vector, one of the main challenges remains to aim for a cell-specific vector. Most probably a vector left in the general circulation without a specific targeting signal, will be sequestered by the liver or may end-up in cells with no need of the