Despite improvements, multiple myeloma (MM) remains an incurable disease, and drug resistance develops eventually. Deep sequencing studies performed in patients with diffuse large B cell lymphoma (DLBCL) or MM identified many novel significantly mutated genes. This chapter provides an overview of the targeted agents in clinical trials for patients with MM and DLBCL. As of August 2014, there were 568 clinical trials listed in the National Institutes of Health registry. Drugs with defined molecular targets are likely to increase in number over the next few years. In addition to small molecule inhibitors, antibodies represent an important class of therapeutics with defined targets. The chapter also talks about new therapeutic challenges revealed by genomics. Strategies to increase initial response rates and reduce drug resistance are under active investigation. MM is preceded in many cases by a premalignant monoclonal gammopathy of undetermined significance (MGUS) phase, which then transitions to smoldering myeloma.