Low iron (Fe) availability critically limits diatom distribution and productivity in vast regions of the modern ocean, such as open-ocean, high nutrient low chlorophyll areas and coastal regimes characterized as Fe limitation ‘mosaics’. While unique strategies of Fe uptake and storage confer competitive advantages to pennate diatoms, the molecular determinants of low Fe acclimation are largely unknown in centric diatoms. We combined genome-wide and targeted comparative transcriptomic analysis with diagnostic biochemistry and in vivo cell staining as a platform to identify the suite of genes involved in acclimation to Fe and associated oxidative stress in Thalassiosira pseudonana. A total of 1312 genes, nearly 12% of the total genome content, responded to Fe starvation in growing cells characterized by low photosynthetic efficiency and enhanced oxidative stress, caspase activity and metacaspase expression. While 82% of the most highly upregulated genes were also represented in EST libraries derived from diverse diatoms grown under various stress conditions (e.g. silicon, CO2 and nitrogen limitation), our analysis suggests that T. pseudonana mounts a unique molecular response to Fe starvation that includes a number of genes distinct from those of the model pennate diatom, Phaeodactylum tricornutum, which diverged ∼90 million years ago. Homologues to ∼50% of the upregulated genes were also identified in a metatranscriptome of eukaryotic phytoplankton communities from a chronically Fe-limited region in the Northeast Pacific. Furthermore, we provide experimental evidence that a subset of putative death-related genes participate in the cellular acclimation to low Fe and associated oxidative damage, suggesting that they co-evolved with other metabolic pathways and play adaptive roles in the success of diatoms.