Various experimental strategies aim to (re)activate p53 signalling in cancer cells. The most advanced clinically are small-molecule inhibitors of the autoregulatory interaction between p53 and MDM2 (murine double minute 2). Different MDM2 inhibitors are currently under investigation in clinical trials. As for other targeted anti-cancer therapy approaches, relatively rapid resistance acquisition may limit the clinical efficacy of MDM2 inhibitors. In particular, MDM2 inhibitors were shown to induce p53 mutations in experimental systems. In the present article, we summarize what is known about MDM2 inhibitors as anti-cancer drugs with a focus on the acquisition of resistance to these compounds.