Immunomodulatory drugs (IMiDs), including lenalidomide and pomalidomide in combination with proteasome inhibitors, dexamethasone and anti-CD38 monoclonal antibodies, play a central role in the treatment of multiple myeloma (MM) across newly diagnosed and relapsed stages. These treatment regimens have significantly improved patient outcomes worldwide, establishing IMiDs as one of the backbones of MM therapy. A new generation of more potent compounds called cereblon E3 ligase modulators (CELMoDs) is now being developed to potentially replace the older IMiDs. In addition, novel immunotherapeutic approaches led by chimeric antigen receptor (CAR T), T-cell engagers and antibody-drug conjugates are also increasingly used in relapsed and refractory myeloma patient care. However, despite these advances, resistance to IMiD-based therapies inevitably develops and represents a major clinical challenge. Understanding the biological basis of resistance to IMiD-based therapy is crucial to plan and maximise treatment options for patients when they relapse on IMiD containing regimens. Emerging evidence underscores the role of genetic and epigenetic alterations, changes in downstream signalling, and dysregulation of the bone marrow immune microenvironment in driving therapeutic resistance. In this review, we explore current literature on the molecular and immune mechanisms related to the onset of therapeutic resistance. We then suggest ways to overcome resistance and exemplify options for the future, focusing on immunotherapy combinations with IMiDs or CELMoDs and novel agents.