MDM2 is considered a hub protein due to its capacity to interact with a large number of different partners of which p53 is most well described. MDM2 is an E3 ubiquitin ligase, and many, but not all, of its interactions relate directly to this activity, such as substrates, adaptors or bridges, promoters, inhibitors or complementary factors. Some interactions serve regulatory functions that in response to cellular stresses control the localisation and functions of MDM2 including protein kinases, ribosomal proteins and proteases. Moreover, interactions with nucleotides serve other functions such as mRNA to regulate protein synthesis and DNA to control transcription. To perform such a pleiotropic panorama of different functions, MDM2 is subjected to a multitude of post-translational modifications and is expressed in different isoforms. The large and diverse interactome is made possible due to the plasticity of MDM2 and in this review we have listed the MDM2 interactions until now and we will discuss how this multifaceted protein can interact with such a variety of substrates to provide a key intermediary role in different signalling pathways.