Cellular phenotype is determined by genetic and microenvironmental factors. There is evidence that tissue oxygenation status is one of the microenvironmental factors regulating cellular behaviour. Both normal and pathological processes such as blastocyst implantation in the uterus, placentation, and rapidly growing tumours occur under conditions characterized by relatively low oxygen levels. In this review, we address the effects of low oxygen concentrations on the phenotype of trophoblast and cancer cells. We provide evidence that oxygenation levels play an important role in the regulation of normal and pathological cellular invasiveness as it occurs during trophoblast invasion of the uterus and in tumour progression and metastasis, drug resistance in cancer, and antitumour activity of natural killer cells of the immune system.