Climatic changes occurring naturally or due to human involvements are a potential threat to global crop production. Flood stress or the water logging which causes submergence is among the major abiotic stresses encountered by plants frequently. Flooding stress causes low cellular oxygen content which affects plant growth particularly when photosynthesis is limited or absent at different developmental stages of their life cycle. Plants use distinct defense mechanisms in response to this challenging stress whereas the biological pathways are similar at the molecular level. In response to the flooding stress, usually plants mediate the changes in their energy metabolism, signaling behaviors, architecture, endogenous phytohormonal biosynthesis, and respiration. However, the knowledge and the selection of the effective gene editing technologies in addition to characterizing and identifying the genes involved in flood stress response is the essential criterion to engineer flood-tolerant crops. In general, the scarcity of O2 in plants results in hypoxia, which inhibits oxidative phosphorylation, making the plants shift to an exclusively substrate-level phosphorylation of ADP to ATP and subsequent glycolysis and fermentation, leading to the accumulation of lactate which is toxic to the plant tissues. Plants are able to respond to low oxygen via ROS sensing and the so-called N-end rule pathway which activates the ERFIV transcription factors leading to downstream activation of hypoxia responsive genes in the nucleus, such as NADPH Oxidases (NOXs), Respiratory Burst Oxidase Homologs (RBOHs), Pyruvate Decarboxylase 1 (PDC1), Dehydrogenase 1(ADH1), and Sucrose Synthase 1. Several transgenic approaches successfully engineered hypoxia tolerant plants including the overexpression of HaHB11, HvERF2.11, VHb in Arabidposis, as well as RBOHH knock-out and HvPRT6 silencing in barley. In this chapter, we briefly describe the current understanding of plants to circumvent hypoxia and molecular pathways and genes involved in low oxygen stress. Furthermore, flood response factors, transgenic approaches to engineering the plant’s tolerance, and the major challenges of future research are also discussed. Future researchers can use this updated picture as treasure trove to understand the basis of flood stress in plants and cover research gaps to develop flood resistance varieties under intense flood conditions.