Tissue hypoxia occurs where there is an imbalance between oxygen supply and consumption. Hypoxia occurs in solid tumours as a result of an inadequate supply of oxygen, due to exponential cellular proliferation and an inefficient vascular supply. It is an adverse prognostic indicator in cancer as it is associated with tumour progression and resistance to therapy. The expression of several genes controlling tumour cell survival are regulated by hypoxia, e.g., growth factors governing the formation of new blood vessels, and hypoxia-responsive transcription factors modulating the expression of genes, which promote tumour cell survival. This review outlines some of the pathways by which tumour hypoxia leads to chemotherapeutic resistance, directly due to lack of oxygen availability, and indirectly due to alterations in the proteome/genome, angiogenesis and pH changes. Some innovative therapies are also detailed which may potentially minimise or eliminate these problems associated with targeting solid tumours.