Multiple myeloma is the most common haematological malignancy yet currently it remains incurable. For decades the mainstay in therapy has been non-targeted approaches including genotoxic agents and immunosuppressants. With myeloma predominantly affecting an elderly population, who are vulnerable to aggressive therapy, these non-specific approaches have resulted in poor survival. However, in recent years an explosion of collaborative research into myeloma has identified molecular interactions between myeloma cells and the bone marrow microenvironment as promoting myeloma development and associated complications such as bone lesions due to osteolysis. At the same time, a better understanding of the adhesion molecules, cytokines and signalling pathways involved in myeloma has led to the development of new targeted therapies, which are improving the quality of life for patients and significantly extending median patient survival. This review explores the current understanding of molecular pathways that promote myeloma progression and lead to bone destruction, with particular reference to the influence of interactions with the bone marrow microenvironment. It describes molecular targets for therapy with reference to the new therapeutics and their improved efficacy. While the outlook for myeloma patients has improved in recent years as a result of these new approaches, drug resistance remains a problem and future therapies will also need to address the molecular mechanisms of resistance in order to improve further the outcome for patients with this disease.