This study investigates the relationship between transcriptional activity and specificity in human transcription factors (TFs). The authors found that human TFs exhibit suboptimal activity and specificity, which is encoded as submaximal dispersion of aromatic residues in their intrinsically disordered protein regions (IDRs). They identified approximately 500 human TFs with short periodic blocks of aromatic residues, similar to imperfect prion-like sequences. Mutating these aromatic residues reduced transcriptional activity, while increasing their dispersion enhanced activity and reprogramming efficiency, promoted liquid-liquid phase separation in vitro, and improved DNA binding in cells. These findings suggest that suboptimal features in TFs may play an important evolutionary role in transcriptional control. The study also proposes that engineering amino acid features to alter phase separation could be a strategy to optimize TF-dependent processes, including cellular reprogramming.This study investigates the relationship between transcriptional activity and specificity in human transcription factors (TFs). The authors found that human TFs exhibit suboptimal activity and specificity, which is encoded as submaximal dispersion of aromatic residues in their intrinsically disordered protein regions (IDRs). They identified approximately 500 human TFs with short periodic blocks of aromatic residues, similar to imperfect prion-like sequences. Mutating these aromatic residues reduced transcriptional activity, while increasing their dispersion enhanced activity and reprogramming efficiency, promoted liquid-liquid phase separation in vitro, and improved DNA binding in cells. These findings suggest that suboptimal features in TFs may play an important evolutionary role in transcriptional control. The study also proposes that engineering amino acid features to alter phase separation could be a strategy to optimize TF-dependent processes, including cellular reprogramming.