Trim-NHL proteins are defined by RING, B-Box and Coiled-coil protein motifs (referred to collectively as the Trim domain) coupled to an NHL domain. The C. elegans, D. melanogaster, mouse and human Trim-NHL proteins are potential and in several cases confirmed, E3 ubiquitin ligases. Current research is focused on identifying targets and pathways for Trim-NHL-mediated ubiquitination and in assessing the contribution of the NHL protein-protein interactiondomain for function and specificity. Several Trim-NHL proteins were discovered in screens for developmental genes in model organisms; mutations in one of the family members, Trim32, cause developmental disturbances in humans. In most instances, mutations that alter protein function map to the NHL domain. The NHL domain is a scaffold for the assembly of a translational repressor complex by the Brat proto-oncogene, a well-studied family member in Drosophila. The link to translational control is common to at least four Trim-NHLs that associate with miRNA pathway proteins. So far, two have been shown to repress (Mei-P26 and Lin41) and two to promote (NHL-2, Trim32) miRNA-mediated gene silencing. In this chapter we will describe structure-function relations for each of the proteins and then focus on the lessons being learned from these proteins about miRNA functions in development and in stem cell biology.