This review provides a revised perspective on protein-DNA interactions, emphasizing the importance of the three-dimensional structures of both proteins and DNA. The authors divide protein-DNA interactions into two categories: base readout, where proteins recognize the unique chemical signatures of DNA bases, and shape readout, where proteins recognize sequence-dependent DNA shape. Base readout is further divided into interactions in the major and minor grooves, while shape readout is subdivided into global and local shape recognition. The review argues that individual DNA binding proteins combine multiple readout mechanisms to achieve specificity, with base readout often distinguishing between families and shape readout providing higher-resolution specificity within families. The authors also discuss the structural motifs used by proteins to bind DNA, the sequence-dependent variations in DNA structure, and the mechanisms by which proteins recognize these structures. They conclude that protein-DNA recognition is a complex process involving a continuum of readout mechanisms, reflecting the fine-tuning of interactions by evolution.This review provides a revised perspective on protein-DNA interactions, emphasizing the importance of the three-dimensional structures of both proteins and DNA. The authors divide protein-DNA interactions into two categories: base readout, where proteins recognize the unique chemical signatures of DNA bases, and shape readout, where proteins recognize sequence-dependent DNA shape. Base readout is further divided into interactions in the major and minor grooves, while shape readout is subdivided into global and local shape recognition. The review argues that individual DNA binding proteins combine multiple readout mechanisms to achieve specificity, with base readout often distinguishing between families and shape readout providing higher-resolution specificity within families. The authors also discuss the structural motifs used by proteins to bind DNA, the sequence-dependent variations in DNA structure, and the mechanisms by which proteins recognize these structures. They conclude that protein-DNA recognition is a complex process involving a continuum of readout mechanisms, reflecting the fine-tuning of interactions by evolution.