Transcription factors (TFs) orchestrate multiple cellular processes through tight regulation via post-translational modifications (PTMs). Thus, decoding the combinations of PTMs should provide critical layer of information that can be integrated into highly specific cellular outputs to reveal a network of genes and their target-specific regulation. Protein modifications play a decisive role in various drug responses and eventually in prognosis for many life-threatening diseases, and recent studies demonstrate that TF-based drug designing must consider structural and functional changes due to PTMs, yet we are just beginning to grasp this enormity and the impact on normal development and disease pathophysiology.