The only group of organisms in which a biological function for cadmium has been shown is the diatoms, which are unicellular phytoplankton. Yet diatoms exhibit similar sensitivity to Cd as other groups of phytoplankton. We have investigated responses of Cd on molecular, metabolic, and physiological levels in the diatom Phaeodactylum tricornutum. P. tricornutum apparently has a high tolerance to Cd; only minor responses were observed on growth, pigment, and transcriptional changes at cadmium concentrations of 123 μg/L. No significant changes in chlorophyll and xanthophyll levels were observed, and the very few transcripts affected strongly indicate that the cells were able to respond to the increased Cd(2+) levels without changing proteins levels. At 10 times this concentration, 1230 μg/L, a much clearer response was observed, including transcripts encoding proteins involved in metal transport, cell signaling, and detoxification processes. Our results point toward putative pathways for the removal or detoxification of Cd and its metabolites as well as a possible Cd uptake mechanism. We predict that ATPase5-1B is involved in removal of Cd by pumping Cd(2+) ions out of the cell, whereas VIT1/CCC1 sequesters Cd(2+) in the vacuole.