This article explores the trade-off between the activity and specificity of transcription factors (TFs) in human cells, revealing that TFs encode submaximal dispersion of aromatic residues in their intrinsically disordered regions (IDRs) to balance these properties. The study identifies approximately 500 human TFs with periodic aromatic residues in their IDRs, resembling imperfect prion-like sequences. Mutation of these residues reduces transcriptional activity, while increasing aromatic dispersion enhances activity and reprogramming efficiency, promotes liquid-liquid phase separation, and increases DNA binding promiscuity. These findings, combined with recent work on enhancer elements, suggest an evolutionary role for suboptimal features in transcriptional control. The study proposes that rational engineering of amino acid features affecting phase separation could optimize TF-dependent processes, including cellular reprogramming. Human TFs establish cell-specific transcriptional programs by binding to DNA elements in enhancers. However, the principles governing how enhancers and TFs interact to produce cell-specific programs are largely unknown. Emerging evidence suggests that critical developmental information is encoded in enhancers that drive weak tissue-specific expression. These weak enhancers contain suboptimal TF-binding motifs and spacing, and mutant enhancers with optimized motifs drive elevated but less specific transcription, leading to developmental defects. These results suggest an important evolutionary trade-off between activity and specificity encoded within weak enhancers, also referred to as 'suboptimization'. Whether such a trade-off is encoded in TFs themselves is unclear. If so, understanding the sequence features that encode such a trade-off could enable the design of natural TF variants with customized cellular reprogramming and other functionalities. The study found that hundreds of TF IDRs encode traces of aromatic periodicity. Optimization of aromatic dispersion enhanced the activity and reduced the specificity of TFs, with consistent changes in in vitro phase separation. Three TF IDRs encoding periodic aromatic blocks were selected for functional testing (HOXB1, HOXD4, and HOXC4). All three purified recombinant monomeric enhanced green fluorescent protein (mEGFP)-tagged IDRs formed droplets in a concentration-dependent manner in the presence of a crowding agent. The droplets underwent fusion and wetted the surface of the microscopy slide, hallmarks of liquid-liquid phase separation. Substitution of aromatic residues reduced droplet formation. As a test of transcriptional activity, the wild-type IDRs fused to the GAL4 DBD activated transcription of a luciferase reporter driven by five repeats of the upstream activation sequence when transfected into various cells. Substitution of aromatic residues virtually abolished activity of all six IDRs tested. The study also found that increasing aromatic dispersion in the HOXD4 IDR enhances its activity. Further mutagenesis of the HOXD4 IDR revealed that increasing the aromatic dispersion enhances transactivation within the confines of additional sequence features but independent of predicted structural elements. The HOXD4 IDR contains a predicted minimal activation domain. A 40-amino-acid fragmentThis article explores the trade-off between the activity and specificity of transcription factors (TFs) in human cells, revealing that TFs encode submaximal dispersion of aromatic residues in their intrinsically disordered regions (IDRs) to balance these properties. The study identifies approximately 500 human TFs with periodic aromatic residues in their IDRs, resembling imperfect prion-like sequences. Mutation of these residues reduces transcriptional activity, while increasing aromatic dispersion enhances activity and reprogramming efficiency, promotes liquid-liquid phase separation, and increases DNA binding promiscuity. These findings, combined with recent work on enhancer elements, suggest an evolutionary role for suboptimal features in transcriptional control. The study proposes that rational engineering of amino acid features affecting phase separation could optimize TF-dependent processes, including cellular reprogramming. Human TFs establish cell-specific transcriptional programs by binding to DNA elements in enhancers. However, the principles governing how enhancers and TFs interact to produce cell-specific programs are largely unknown. Emerging evidence suggests that critical developmental information is encoded in enhancers that drive weak tissue-specific expression. These weak enhancers contain suboptimal TF-binding motifs and spacing, and mutant enhancers with optimized motifs drive elevated but less specific transcription, leading to developmental defects. These results suggest an important evolutionary trade-off between activity and specificity encoded within weak enhancers, also referred to as 'suboptimization'. Whether such a trade-off is encoded in TFs themselves is unclear. If so, understanding the sequence features that encode such a trade-off could enable the design of natural TF variants with customized cellular reprogramming and other functionalities. The study found that hundreds of TF IDRs encode traces of aromatic periodicity. Optimization of aromatic dispersion enhanced the activity and reduced the specificity of TFs, with consistent changes in in vitro phase separation. Three TF IDRs encoding periodic aromatic blocks were selected for functional testing (HOXB1, HOXD4, and HOXC4). All three purified recombinant monomeric enhanced green fluorescent protein (mEGFP)-tagged IDRs formed droplets in a concentration-dependent manner in the presence of a crowding agent. The droplets underwent fusion and wetted the surface of the microscopy slide, hallmarks of liquid-liquid phase separation. Substitution of aromatic residues reduced droplet formation. As a test of transcriptional activity, the wild-type IDRs fused to the GAL4 DBD activated transcription of a luciferase reporter driven by five repeats of the upstream activation sequence when transfected into various cells. Substitution of aromatic residues virtually abolished activity of all six IDRs tested. The study also found that increasing aromatic dispersion in the HOXD4 IDR enhances its activity. Further mutagenesis of the HOXD4 IDR revealed that increasing the aromatic dispersion enhances transactivation within the confines of additional sequence features but independent of predicted structural elements. The HOXD4 IDR contains a predicted minimal activation domain. A 40-amino-acid fragment