TRIM proteins are multidomain proteins that typically assemble into large molecular complexes, the composition of which likely explains the diverse functions that have been attributed to this group of proteins. Accumulating data on the roles of many TRIM proteins supports the notion that those that share identical C-terminal domain architectures participate in the regulation of similar cellular processes. At least nine different C-terminal domain compositions have been identified. This chapter will focus on one subgroup that possess a COS motif, FNIII and SPRY/B30.2 domain as their C-terminal domain arrangement. This C-terminal domain architecture plays a key role in the interaction of all six members of this subgroup with the microtubule cytoskeleton. Accumulating evidence on the functions of some of these proteins will be discussed to highlight the emerging similarities in the cellular events in which they participate.