The TrkB neurotrophin receptor is critical for normal development of the nervous system and other tissues. We show here by real-time RT-PCR that TrkB mRNA levels in human neuroblastoma cells (Kelly) were elevated more than 10-fold under hypoxia (1 % O₂) and with the hypoxia mimetic 2,2'-dipyridyl (DP, 100 mM) at normoxia (20 % O ₂). Likewise, a 2.5 kb TrkB promoter-reporter construct was exquisitely sensitive to activation by hypoxia and DP in transiently transfected neuroblastoma cells. Hypoxia sensitivity of the TrkB promoter was confined to a region between -969 and -784 bp relative to the transcription start site. This sequence contained three predicted binding motifs for hypoxia-inducible factor-1, HIF-1. Knockdown of HIF-1a by siRNA transfection reduced significantly TrkB expression in neuroblastoma cells during DP treatment. Exposure of rats to hypoxia (8 % O₂, 8 h) enhanced TrkB expression in the heart and lung, but not in other tissues studied. These findings demonstrate that hypoxia is a physiological stimulus for the expression of the TrkB neurotrophin receptor in vitro and in vivo. Furthermore, TrkB expression under hypoxia appears to involve hypoxia-inducible factor-1, HIF-1. It is suggested that hypoxic activation of the TrkB receptor has a role in neuronal tumor cell growth and normal tissue function.