Because of safety issues, components of the beta-adrenergic signaling pathway cannot currently be viewed as attractive targets for human gene therapy. Rather, the balance of evidence supports strategies that will target gene products specifically and directly at diastolic regulation. Augmenting the activity of the SR Ca2+ ATPase by AAV-mediated delivery of the SERCA2a gene, directed by a cardiac-specific promoter with a tightly regulable on-off switch is perhaps the most attractive strategy. PLB and cTnI also are attractive targets but only if molecular techniques can be devised to modulate their activity specifically and conditionally. Such techniques may involve modifying the phosphorylation sites in vitro and replacing wild type proteins in the failing heart with the modified forms, again using regulated AAV vectors for gene delivery.