Multiple myeloma (MM) is a hematologic malignancy that is considered mostly incurable in large part due to the inability of standard of care therapies to overcome refractory disease and inevitable drug-resistant relapse. The post-genomic era has been a productive period of discovery where modern sequencing methods have been applied to large MM patient cohorts to modernize our current perception of myeloma pathobiology and establish an appreciation for the vast heterogeneity that exists between and within MM patients. Numerous pre-clinical studies conducted in the last two decades have unveiled a compendium of mechanisms by which malignant plasma cells can escape standard therapies, many of which have potentially quantifiable biomarkers. Exhaustive pre-clinical efforts have evaluated countless putative anti-MM therapeutic agents and many of these have begun to enter clinical trial evaluation. While the palette of available anti-MM therapies is continuing to expand it is also clear that malignant plasma cells still have mechanistic avenues by which they can evade even the most promising new therapies. It is therefore becoming increasingly clear that there is an outstanding need to develop and employ precision medicine strategies in MM management that harness emerging tumor profiling technologies to identify biomarkers that predict efficacy or resistance within an individual’s sub-clonally heterogeneous tumor. In this review we present an updated overview of broad classes of therapeutic resistance mechanisms and describe selected examples of putative biomarkers. We also outline several emerging tumor profiling technologies that have the potential to accurately quantify biomarkers for therapeutic sensitivity and resistance at genomic, transcriptomic and proteomic levels. Finally, we comment on the future of implementation for precision medicine strategies in MM and the clear need for a paradigm shift in clinical trial design and disease management.