Numerous treatments are available for relapsed and/or refractory multiple myeloma (MM), with safety profiles varying across drug classes and across agents within the same class. Thus, it is important to understand the toxicities of each antimyeloma agent when making treatment decisions. Neutropenia is commonly associated with lenalidomide and pomalidomide, and may be common with histone deacetylase (HDAC) inhibitors, but is relatively unusual with thalidomide, bortezomib, and carfilzomib. Infection was common in trials of lenalidomide and pomalidomide, and upper respiratory tract infection and pneumonia have been seen with carfilzomib. Cardiac toxicity was observed with thalidomide and may occur with proteasome inhibition. Thromboembolic complications occur with thalidomide and its derivatives, but are less common with bortezomib. Peripheral neuropathy (PN), an important complication of MM, may be exacerbated by bortezomib and thalidomide, and was also observed with lenalidomide. In contrast, PN is rarely observed with carfilzomib and pomalidomide. Renal impairment reduces the clearance of lenalidomide but does not seem to affect substantially the pharmacokinetics of pomalidomide, carfilzomib, or bortezomib. Several therapies have recently been approved, such as the oral proteasome inhibitor ixazomib, the HDAC inhibitor panobinostat, and the monoclonal antibodies elotuzumab and daratumumab. Others are still in clinical development, including the HDAC inhibitors romidepsin and vorinostat, with safety data continuing to emerge. Therapy decisions should consider safety profiles in association with pre-existing comorbidities and toxicities from previous therapeutic regimens. Optimal treatment selection and the management of toxicities will result in fewer patients requiring dose reductions and treatment discontinuations, ultimately leading to improved outcomes.