The IKK [inhibitor of NF-kappaB (nuclear factor kappaB) kinase] complex has an essential role in the activation of the family of NF-kappaB transcription factors in response to a variety of stimuli. To identify novel IKK-interacting proteins, we performed an unbiased proteomics screen where we identified TfR1 (transferrin receptor 1). TfR1 is required for transferrin binding and internalization and ultimately for iron homoeostasis. TfR1 depletion does not lead to changes in IKK subunit protein levels; however, it does reduce the formation of the IKK complex, and inhibits TNFalpha (tumour necrosis factor alpha)-induced NF-kappaB-dependent transcription. We find that, in the absence of TfR1, NF-kappaB does not translocate to the nucleus efficiently, and there is a reduction in the binding to target gene promoters and consequentially less target gene activation. Significantly, depletion of TfR1 results in an increase in apoptosis in response to TNFalpha treatment, which is rescued by elevating the levels of RelA/NF-kappaB. Taken together, these results indicate a new function for TfR1 in the control of IKK and NF-kappaB. Our data indicate that IKK-NF-kappaB responds to changes in iron within the cell.