Our data indicate that: i) 1% O2 hypoxia protects cells from etoposide-induced cell death through an early ROS delivery by mitochondria; ii) this leads to a redox stabilization of HIF-1 leading to autocrine secretion of VEGF-A; iii) VEGF-A acts as a survival factor for melanoma cells through interaction with its receptor VEGFR2, leading to generation of a second wave of ROS through NADPH oxidase, which ultimately causes a long lasting HIF-1 stabilization, enhancing melanoma cell survival to etoposide chemotherapy. Here, FMO5 is linked to melanoma.