Abstract: Multiple myeloma (MM) is a highly heterogeneous and refractory plasma cell tumor. It is similar to most solid tumors in the hypoxic tumor microenvironment (TME) it is exposed to, promoting hypoxia inducible factor-1 (HIF-1) activation and related transcription factors of the corresponding downstream signaling pathways, affecting tumor angiogenesis, myeloma cell dissemination and metastasis, anti-tumor immunity, tumor immune escape promotion as well as altering the cellular energy metabolism and participating in therapeutic resistance induction. In this study, based on the above-described mechanisms, we aim at reviewing the current research status of hypoxic microenvironment-targeting therapies in MM treatment, focusing on the direct inhibition of HIF factors or signaling pathway targeting; metabolism improvement and oxygenation increase; effective tumor immunity restoration by targeting immune checkpoints; anti-angiogenesis. Precise hypoxia targeting combined with standardized therapy offers a promising strategy and research hotspot in MM therapy.