The oxygen availability to plant tissues can vary strongly in time and space. To endure short- or long-term oxygen deprivation, plants evolved a series of metabolic and morphological adaptations that have been extensively studied. However, our knowledge of the molecular regulation of these processes is not as well understood. In this review, the recent findings on the molecular effectors that regulate the response of higher plants to oxygen deficiency are discussed. Although no direct oxygen sensor has been discovered in plants so far, mechanisms that perceive low-oxygen derived signals have been reported, involving different sets of transcription factors (TFs). The ERF (Ethylene Responsive Factor) family especially appears to play a crucial role in the determination of survival to reduced oxygen availability in Arabidopsis and rice. This class of TFs displays a broad range of targets, being involved in both the metabolic reprogramming and the morphological adaptations exploited by plants when subjected to low-oxygen conditions.