Transcription factors (TFs) constitute a class of proteins that regulate gene transcription through sequence-specific DNA binding and thereby govern a broad spectrum of cellular processes and functions. Recent rapid advances in structural pharmacology have substantially enhanced mechanistic understanding of TF conformational transitions, ligand recognition features, and interaction networks with coregulatory partners, establishing a critical structural framework for rational targeted drug design. Nuclear receptors represent a structurally conserved yet functionally diverse family of ligand-regulated TFs that are extensively involved in major physiological and pathological processes, including development, metabolism, immunity, inflammation, and tumorigenesis. This review systematically summarizes the domain organization of prototypical nuclear receptors and the conformational characteristics of their ligand-binding domains, and highlights recent progress in nuclear receptor structural pharmacology. It further examines the structural basis and therapeutic potential of "nuclear receptor-like" family proteins as emerging drug targets, with representative examples drawn from hypoxia-inducible factors (HIF) and the aryl hydrocarbon receptor (AHR). In addition, advances in structure-guided discovery of compounds targeting other TF systems, including STAT3, p53/MDM2, and MYC/MAX, are discussed. Finally, the review provides a forward-looking perspective on the application of emerging technologies, such as AI-assisted structure prediction and dynamic conformational simulation, in TF-targeted drug discovery.