Hypoxia as one of the most prominent features in tumors, has presented negative effects on tumor therapies including photodynamic therapy, radiotherapy, and chemotherapies, leading to the tumor regeneration and metastasis. Recently, nanomedicines have been proposed to handle the hypoxia dilemma. Some nanomedicines alleviated hypoxia to enhance the therapeutic effect, others used hypoxia-sensitive substances to treat tumor. Among them, macromolecular nanomaterials-based nanomedicine has attracted increased research interest. However, the complicated tumor microenvironment disturbs the practical application of macromolecular nanomaterials to deal with hypoxia. This review highlights the influence of hypoxia on tumor therapy and some new strategies of using macromolecular nanomaterials to overcome hypoxia for effective tumor therapy.