Since most cells do not naturally incorporate foreign DNA, strategies for arterial gene transfer have generally relied on agents designed to augment cellular DNA uptake such as liposomes, viral vectors, and protein conjugates. However, even when DNA has been successfully introduced into a cell, the likelihood of gene expression remains uncertain because the transgene has to escape lysosomal degradation, be transferred to the nucleus for transcription of mRNA, and be exported to the cytoplasm for translation and/or post-translation modification of the protein product. Transfection efficiency represents the final index of this regulatory sequence. The extent to which this compromises human gene therapy for cardiovascular disease depends in part on the presence or absence of a signal sequence permitting active secretion of the gene product. The implication of these issues is discussed with regard to restenosis and angiogenesis.