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 interaction domain 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.