Advances in diglycine remnant affinity enrichment techniques have seen ubiquitylation studies enjoy a significant amount of attention in recent proteomic research.  Here we report our findings from experiments aimed at identifying targets of the HECT E3 ubiquitin ligase, Nedd4.  We have previously shown Nedd4 plays a critical role in neural crest cell development.  Our studies in Nedd4^-/- mice reveal striking defects in the development of neural crest cell derived tissues, including craniofacial and cardiac.  In combination with in vitro data, these studies implicate Nedd4 as an important factor in the maintenance of neural crest cell identity, survival and/or stemness.  To begin addressing how neural crest cells are affected by loss of Nedd4, we needed a workflow to identify targets.  To this end, we have carried out siRNA knockdown of Nedd4 in a SILAC labeled neural crest cell line and used a diglycine remnant enrichment strategy to reveal diglycine peptides that are less abundant following Nedd4 knockdown compared to controls.  We compare these data to total protein abundance data gathered from samples by LC-MS/MS prior to diglycine remnant enrichment, to discern changes specifically in diglycine peptide abundance from changes in total protein.  And finally, we cross check our proteomic data to expression data obtained from the same experimental model to better distinguish whether changes in protein abundance arise from changes in stability or from changes in gene expression.  Taken together, we present a workflow for the identification of protein targets of E3 ubiquitin ligases and reveal a number of interesting and novel putative Nedd4 targets.