Introduction: Cereblon (CRBN), the substrate receptor of the CRL4^CRBN E3 ubiquitin ligase has been extensively studied due to its involvement in many biological processes. It has also been identified as the target for immunomodulatory drugs (IMiDs). CRBN ligands are also important components of proteolysis-targeting chimeras (PROTACs), special bifunctional constructs capable of targeted degradation of aberrantly acting proteins using the cell’s ubiquitin-proteasome machinery. Areas covered: Due to upsurge of the PROTAC technology, the patenting activity of new CRBN ligands has been on the rise in the last 5 years. The present review covers two broadly defined areas of CRBN ligand design. One covers ‘thalidomide-like’ molecules representing modifications of various parts of classical IMiDs. The other areas–non-thalidomide-like compounds–are compounds that are structurally distinct from the classical IMiDs. Efforts toward creating new CRBN ligands reflected in non-patent literature are briefly discussed with emphasis on the rational, crystallography-driven approaches. Expert opinion: The chemical space of CRBN ligands which is related to the classical IMiDs (thalidomide/lenalidomide/pomalidomide) is comprehensively covered by the current patent literature. The promising area of research is in the identification of non-thalidomide-like chemotypes capable of binding to CRBN. Rational, crystallography-driven approaches currently exploited in academia will significantly aid in this endeavor.