The TRIM family is composed of multidomain ubiquitin E3 ligases characterized by the presence of the N‐terminal tripartite motif (RING, B‐boxes, and coiled coil). TRIM proteins transfer the ubiquitin moiety to specific substrates but are also involved in ubiquitin‐like modifications, in particular SUMOylation and ISGylation. The TRIM family members are involved in a plethora of biological and physiological processes and, when altered, are implicated in many pathological conditions. Growing evidence indicates the pleiotropic effect of several TRIM genes, each of which might be connected to very diverse cellular processes. As a way to reconcile a single family member with several functions, we propose that structural features, that is, their ability to homo‐ and hetero‐di(multi)merize, can increase and diversify TRIM ubiquitin E3 ligase capability. © 2011 IUBMB Life, 2011