At present retroviral vectors (RV) of both the gamma-retroviral (γ-RV) and lentiviral vector (LV) class with their ability to integrate their genetic material into the target cell genome, currently remain the most efficient and thus the system of choice for achieving transgene retention and therefore potentially long-term expression and therapeutic benefit. However, γ-RV and LV integration comes at a cost in that transcription units will be present within a native chromatin environment and thus be subject to epigenetic effects (DNA methylation, histone modifications) that can negatively impact on their function. Indeed, highly variable expression and silencing of γ-RV and LV transgenes especially resulting from promoter DNA methylation is well documented and was the cause of the failure of gene therapy in a clinical trial for X-linked chronic granulomatous disease. This review will critically explore the use of different classes of genetic control elements that can in principle reduce vector insertion site position effects and epigenetic-mediated silencing. These transcriptional regulatory elements broadly divide themselves into those with either a chromatin boundary or border function (scaffold/matrix attachment regions, S/MARS; insulators) and those with a dominant chromatin remodelling and transcriptional activating capability (locus control regions, LCRs; ubiquitous chromatin opening elements, UCOEs). All these types of elements have their strengths and weaknesses within the constraints of a γ-RV and LV backbone, showing varying degrees of efficacy in improving reproducibility and stability of transgene function. Combinations of boundary and chromatin remodelling, transcriptional activating elements, which do not impede vector production, transduction efficiency and stability are most likely to meet the requirements within a gene therapy context especially when targeting a stem cell population.