CRISPR technology is being used to define mechanisms of multiple myeloma (MM) drug resistance. Here, Constantine Mitsiades, MD, PhD, of the Dana-Farber Cancer Institute, Boston, MA, discusses his group’s work in this exciting area, investigating Cereblon pathway-mediated resistance to thalidomide and its derivatives, lenalidomide and pomalidomide. He concludes by highlighting what can be done in future trials to select patients who do not have this resistance. This interview took place at the Myeloma 2018 meeting, held in San Diego, CA.