Human NPAS2 is a basic-helix-loop-helix (BHLH) transcription factor with two N-terminal PAS domains that forms a hetero-dimeric complex with BMAL1/ARNTL to regulate the transcription of key circadian clock genes like Period and Cryptochrome. NPAS2 is unique in higher eukaryotic cells as both PAS domains contain one heme group each, which bind carbon monoxide. Although NPAS2 has been linked to cancer and neurological disorders, very little is known about its cellular roles. The results obtained in this study support a model in which NPAS2 responds to oxidative and heat stress in distinct manners. While oxidative stress results in the post-translational modification of NPAS2 and the formation of high molecular weight complexes, heat stress reduces the protein levels of NPAS2. These differences are also reflected in the changes to the NPAS2 mRNA levels. While oxidative stress increases expression of NPAS2, heat stress causes a drop in mRNA levels. The responses are cell line specific as, for example, the drop in NPAS2 protein levels after a heat shock was observed in MCF-7 breast cancer cells and HeLa cervical cancer cells, but not in non-malignant HEK-293 cells which may be of neuronal origin. Since both stress types are known to affect the peripheral clocks in human tissues in a manner which may be regulated by the MAP kinase p38β, it is proposed that NPAS2 is a novel target of this kinase. Why NPAS2 is regulated differently depending on the type of stress, could be linked with the different ways the p38 MAP kinase pathway responds to heat and oxidative stress. While heat activation is dependent on upstream kinases, heat activation may be dependent on the heat-induced increase in carbon monoxide in human cells. The works shows also that NPAS2 mRNA levels drop in the response to serum starvation and that the neuroblastoma KELLY cell line does not, or only at a very reduced level, express NPAS2 although an analysis of a large panel of human tissues shows high NPAS2 expression in the brain. A bioinformatical analysis of missense single nucleotide polymorphisms (SNPs) located the N-terminal domain of NPAS2 identifies two SNPs (S204P, rs750277651 and T252N, rs555063320) which may affect a p38 (S202) and EYRK1A (T252) kinase modification site, respectively. This is of interest as p38β may regulate NPAS2 and the dual-specific DYRK1A kinase is known to regulate the protein turnover of Cryptochrome. In summary, the work makes a strong case for NPAS2 as a novel target of the p38β MAP kinase pathway in the cellular response to oxidative and heat stress.