Knowledge of the plasma selenium levels associated with optimised concentration or activity of specific selenoproteins can provide considerable insights from epidemiological data on the possible involvement of those selenoproteins in health, most notably with respect to cancer. For cohort studies, if selenoproteins such as glutathione peroxidase and selenoprotein P are relevant to cancer, one might only expect to see an effect on risk when the concentrations in the cohort range from below, to above, the level needed to optimise the activity or concentration of these enzymes. Similarly, trials would only show a beneficial effect of supplementation if selenium status were raised from below, to above, the optimal concentration for the selenoproteins likely to be implicated in cancer risk, as occurred in the NPC trial but not in SELECT. The most powerful evidence for the involvement of selenoproteins in human health comes from epidemiological studies that have related single nucleotide polymorphisms in selenoproteins to disease risk. The totality of the evidence currently implicates GPx1, GPx4, SEPS1, Sep15, SEPP1 and TXNRD1 in conditions such as cardiovascular disease, pre-eclampsia and cancer. Future studies therefore need to determine not only selenium status, but genotype, both in selenoproteins and related pathways, when investigating the relationship of selenium with disease risk.