The increasing susceptibility of plants to various abiotic stresses adversely affect the plant growth and development as well as productivity of major crops. Drought has a considerable threat to sustainable agriculture and the global food security due to global warming and climate change. Drought stress decreases the plant growth by affecting various physiological and biochemical functions including photosynthesis, nutrient metabolism, respiration, reactive oxygen species generation. Several drought stress-responsive genes, playing metabolic or regulatory roles, have been identified and characterized in plants using modern genetics and genomic approaches including transcriptomics and proteomics. Transcription factors (TFs), including NAC, WRKY, AP2/ERF, MYB, are regulatory genes that have important roles in response to stress by regulating the downstream stress-responsive genes. NACs are unique plant TFs and have essential regulatory roles in abiotic and biotic stress responses, and plant development. The purpose of this chapter is to summarize the current knowledge of drought stress and function of NAC transcription factors in response to drought stress in plants. The determination of NAC function and relationship with other stress-responsive genes in drought stress will continue to be a major challenge in the coming years.