Zinc-finger nucleases (ZFNs) are a powerful tool that can be used to edit the 
human genome ad libitum. The technology has experienced remarkable development 
in the last few years with regard to both the target site specificity and the 
engineering platforms used to generate zinc-finger proteins. As a result, two 
phase I clinical trials aimed at knocking out the CCR5 receptor in T cells 
isolated from HIV patients to protect these lymphocytes from infection with the 
virus have been initiated. Moreover, ZFNs have been successfully employed to 
knockout or correct disease-related genes in human stem cells, including 
hematopoietic precursor cells and induced pluripotent stem cells. Targeted 
genome engineering approaches in multipotent and pluripotent stem cells hold 
great promise for future strategies geared toward correcting inborn mutations 
for personalized cell replacement therapies. This review describes how ZFNs have 
been applied to models of gene therapy, discusses the opportunities and the 
risks associated with this novel technology, and suggests future directions for 
their safe application in therapeutic genome engineering.