Replication-deficient retroviruses have been successfully utilized as vectors, offering an efficient, stable method of therapeutic gene delivery. Many examples exist proving this mode of integrative gene transfer is both effective and safe in cultured systems and clinical trials. Along with their success, severe side effects have occurred with early retroviral vectors causing a shift in the approach to vector design before further clinical testing. Several alternative delivery methods are available but lentiviral vectors (LV) are among the most favorable as they are already well understood. LV offer safer integration site selection profiles and a lower degree of genotoxicity, compared with γ-retroviral vectors. Following their introduction, development of the self-inactivating vector configuration was a huge step to this mode of therapy but did not confer full protection against insertional mutagenesis. As a result integration, modeling must be improved to eventually avoid this possibility. The cellular factor LEDGF/p75 seems to play an essential role in the process of LV site selection and its interactions with chromatin are being quickly resolved. LEDGF/p75 is at the center of one example directed integration effort where recombinant products bias the integration event, a step toward fully directed integration into pre-determined benign loci. A more accurate picture of the details of LEDGF/p75 in the natural integration process is emerging, including new binding specificities, chromatin interaction kinetics and additional cellular factors. Together with next-generation sequencing technology and bio-informatics to analyze integration patterns, these advancements will lead to highly focused directed integration, accelerating wide-spread acceptance of LV for gene therapy.