Multiple myeloma (MM) is the second most frequent hematological malignancy in the western world, and is characterized by the infiltration and clonal proliferation of antibody-secreting plasma cells in the bone marrow. Therapeutic options for MM have rapidly evolved over the past years. Despite the high initial efficacy of these new combination treatments, the majority of MM patients relapse and become refractory to therapy, due to clonal evolution and selection. This highlights the need for novel and more effective therapies. The translational research described in this thesis focuses on targeting pro-survival signaling pathways in MM. Targeting pro-survival signaling pathways that drive or support oncogenic behavior of cancer cells is a promising therapeutic strategy. The foremost complexity in applying similar strategies for the treatment of MM is the heterogeneity of disease, both on the genetic level, and due to reciprocal interaction with the bone marrow microenvironment. By analyzing both immortalized myeloma cell lines and primary patient samples, we mapped the activity of pro-survival signaling pathways at diagnosis and during disease progression, and assessed the targetability of these pathways by both conventional and new therapeutic agents. By downstream pathway inhibition using synergistic drug combinations, we show the potential to target these pro-survival pathways in a personalized manner, to improve patient outcome and reduce side effects.