Low oxygen pressure or hypoxia is often an obstacle in pathological conditions, including during cancer development and metastatic dissemination. The main family of transcription factors involved in the adaptation to inappropriate oxygen levels are the 'Hypoxia-Inducible Factors' (HIFs) that together with HIF prolyl hydroxylases (PHDs) regulate many different processes, during physiological as well pathological conditions. Additionally, the entire HIF transcription cascade is involved in the 'seventh' hallmark of cancer; tumor promoting inflammation. Previous work revealed that HIF-pathway proteins influence tumor associated immune cells in their action toward proliferation, differentiation, vessel normalization and tumor dissemination. These changes are not necessarily analogous to the role of these proteins in non-tumor related immune responses, where hypoxia often encourages a strong inflammatory response. Recently, Clever et al. demonstrated that T-cell intrinsic inhibition of all three PHDs (PHD1-3) is necessary but sufficient to limit CD4(+)-regulatory T (T-reg) cell induction and stimulates CD8(+) T cell effector function. Interestingly, this resulted in the inhibition of local tolerance in the lung but reduced tumor colonization. In this perspective, we discuss the effect of targeting HIF-pathway proteins in tumor-associated cell lineages, their therapeutic prospective and possible pitfalls.