Hypoxia, the drop in tissue oxygenation, holds a poor prognostic value in different clinicopathologic settings. In solid tumors, hypoxia induces a series of genetic mutations and drives metabolic rewiring in a way that favors cancer progression. Ceramide, the central hub of sphingolipid metabolism, emerged as a major responder to cellular stresses including hypoxia. Although different enzymes take part in ceramide production and catabolism, a particular enzyme of the de novo biosynthesis, dihydroceramide desaturase (DEGS), appears to majorly sense oxygen variations due to its redox properties. In this chapter, we provide a brief overview of key sphingolipid enzymes that respond to hypoxia in acute and chronic clinical settings. We give particular emphasis to the DEGS responses that guide the metabolic adaptation to chronic hypoxia. Understanding the biochemical characteristics of the sphingolipid enzymes in chronic vs. acute hypoxia holds a great promise in turning this knowledge into efficacious clinical products in different pathological contexts.