Artificial transcription factors (ATFs) are potentially a powerful molecular tool to modulate endogenous target gene expression in living cells and organisms. To date, many DNA-binding molecules have been developed as the DNA-binding domains for ATFs. Among them, ATFs comprising Cys₂His₂-type zinc-finger proteins (ZFPs) as the DNA-binding domain have been extensively explored. The zinc-finger-based ATFs specifically recognize targeting sites in chromosomes and effectively up- and downregulate expression of their target genes not only in vitro, but also in vivo. In this review, after briefly introducing Cys₂His₂-type ZFPs, I will review the studies of endogenous human gene regulation by zinc-finger-based ATFs and other applications as well.