Although large amounts of reactive oxygen species (ROS) can be detrimental to a cell, moderate levels are important for the regulation of various cellular processes. When produced in defined subcellular compartments, ROS act locally to specifically modulate signalling pathways and cellular responses, but the mechanisms that underlie such regulation have not yet been elucidated. On page 3695, Ivo Touw and colleagues now show that signalling from the granulocyte colony stimulating factor receptor (GCSFR) is affected by ROS, and that the ER-resident antioxidant peroxiredoxin 4 (PRDX4) and the protein tyrosine phosphatase 1b (PTP1B) are involved in this regulation. PRDX4 primarily resides in the ER and ER–Golgi intermediate compartments (ERGIC), and interacts with the cytoplasmic domain of activated GCSFRs on endosomes, thereby attenuating GCSF-induced STAT3 activation and proliferation in myeloid progenitors. The oxidation-sensitive phosphatase PTP1B also interacts with the GCSFR and inhibits GCSF-induced signalling from early endosomes by reducing the levels of receptor phosphorylation. PTP1B seems to be a downstream target of PRDX4, and the authors propose that, PRDX4 eliminates ROS, which – in turn – counteracts the inhibition of PTP1B by these molecules and, hence, leads to signal attenuation.