Numerous human diseases are caused by changes in gene expression levels. In addition, changing the expression levels of specific genes can lead to therapeutic benefits for several diseases. Systems using nuclease-deficient gene-editing proteins fused to transcriptional modulators that target gene regulatory elements have emerged as powerful, programmable, and customizable systems to modify gene expression for therapeutic benefits. Several of these systems have already been used in the clinic, and many more are under development. Here, we review these emerging technologies and assess their therapeutic potential, their delivery, and related challenges in the clinic.