Meganucleases are sequence-specific endonucleases recognizing large (>12 bp) sequence sites and several laboratories have used these proteins to induce highly efficient gene targeting in mammalian cells. The recent development of artificial endonucleases with tailored specificities has opened the door for a wide range of new applications, including therapeutic ones: redesigned endonucleases cleaving chosen sequences could be used to in gene therapy to correct mutated genes or introduce transgenes in chosen loci. Such "targeted" approaches markedly differ from current gene therapy strategies based on the random insertion of a complementing virus-borne transgene. As a consequence, they should bypass the odds of random insertion. Artificial fusion proteins including Zinc-Finger binding domains have provided important proofs of concept, however the toxicity of these proteins is still an issue. Today custom-designed homing endonucleases, the natural meganucleases, could represent an efficient alternative. After a brief description of the origin of the technology, current systems based on redesigned endonucleases will be presented, with a special emphasis on the recent advances in homing endonuclease engineering. Finally, we will discuss the main issues that will need to be addressed in order to bring this promising technology to the patient.