In this chapter, we will first explore the mechanisms by which different types of proteins detect and respond to levels of lipids, amino acids, and carbohydrates. Following this, we will introduce a fascinating family of ligand-inducible transcription factors known as nuclear receptors. For over 30 years, nuclear receptors have served as models for understanding various functional and structural aspects of transcription factors, including interactions with coactivator and corepressor proteins. The 48 human members of this largest family of transcription factors in metazoans have a unique ability to be specifically activated by small lipophilic ligands approximately the size of cholesterol (about 400 Da). Some of these ligands function as endocrine hormones, such as estradiol and testosterone, while others are metabolites of dietary compounds, like fatty acids and cholesterol. Both types of lipids have significant physiological impacts on health and disease, influencing metabolic regulation and immune modulation. Understanding nutrient sensing, including nuclear receptors, will provide an integrative view of molecular reactions to dietary molecules, addressing cross-regulation between nutrient-sensing pathways and other signaling pathways involved in growth and metabolic disease-related inflammation.