Multiple myeloma (MM) is a debilitating disease of proliferating and malignant plasma cells that is currently incurable. The ability of monoclonal recurrence of disease suggests it might arise from a stem cell-like population capable of self-renewal. The difficulty to isolate the cancer stem-like cell in MM has introduced confusion toward this hypothesis. However, recent evidence has suggested that MM originates from the B cell lineage with memory-B cell like features, allowing for self-renewal of the progenitor-like status and differentiation to a monoclonal plasma cell population. Furthermore, this tumor-initiating cell uses signaling pathways and microenvironment similar to the hematopoietic stem cell, though hijacking these mechanisms to create and favor a more tumorigenic environment. The bone marrow niche allows for pertinent evasion, either through avoiding immunosurveillance or through direct interaction with the stroma, inducing quiescence and thus drug resistance. Understanding the interaction of the MM stem cell to the microenvironment and the mechanisms utilized by various stem cell-like populations to allow persistence and therapy-resistance can enable for better targeting of this cell population and potential eradication of the disease.