Transcription factors (TFs) are key cellular components that control gene expression.They recognize specific DNA sequences,the TF binding sites (TFBSs),and thus are targeted to specific regions of the genome where they can recruit transcriptional co-factors and/or chromatin regulators to fine-tune spatiotemporal gene regulation.Therefore,the identification of TFBSs in genomic sequences and their subsequent quantitative modeling is of crucial importance for understanding and predicting gene expression.Here,we review how TFBSs can be determined experimentally,how the TFBS models can be constructed in silico,and how they can be optimized by taking into account features such as position interdependence within TFBSs,DNA shape,and/or by introducing state-of-the-art computational algorithms such as deep leaing methods.In addition,we discuss the integration of context variables into the TFBS modeling,including nucleosome positioning,chromatin states,methylation pattes,3D genome architectures,and TF cooperative binding,in order to better predict TF binding under cellular contexts.Finally,we explore the possibilities of combining the optimized TFBS model with technological advances,such as targeted TFBS perturbation by CRISPR,to better understand gene regulation,evolution,and plant diversity.