Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. In this study we utilized a conditional Mdm2 allele, Mdm2^FM, and a CAG–CreER tamoxifen‐inducible recombination system to examine the effects of global Mdm2 loss in adult mice. Two different tamoxifen injection regimens caused 100% lethality of Mdm2^FM/−;CAG–CreER mice; both radio‐sensitive and radio‐insensitive tissues were impaired. Strikingly, a large number of radio‐insensitive tissues, including the kidney, liver, heart, retina and hippocampus, exhibited various pathological defects. Similar tamoxifen injections in older (16–18 month‐old) Mdm2^FM/−;CAG–CreER mice yielded abnormalities only in the kidney. In addition, transcriptional activation of Cdkn1a (p21), Bbc3 (Puma) and multiple senescence markers in young (2–4 month‐old) mice following loss of Mdm2 was dampened in older mice. All phenotypes were p53‐dependent, as Mdm2^FM/−;Trp53^−/−;CAG–CreER mice subjected to the same tamoxifen regimens were normal. Our findings implicate numerous possible toxicities in many normal tissues upon use of cancer therapies that aim to inhibit Mdm2 in tumours with wild‐type p53. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.