Many therapeutic strategies for end-stage renal disease (ESRD) patients have failed to exhibit survival improvement in large-scale randomized controlled trials (RCTs). The current review gives an overview on the medical strategies for treatment of ESRD patients that have previously been tested in RCTs with mortality reduction as pre-specified study endpoint. We identified 19 RCTs with the following therapeutic strategies: haematocrit increase by erythropoietin (n = 1), growth hormone application (n = 1), lipid-lowering by statins (n = 3), renin-angiotensin system blockage (n = 4), β-receptor blockage (n = 1), homocysteine lowering (n = 5), application of anti-oxidative substances (n = 2), omega-3-fatty-acid supplementation (n = 1) and calcium-free phosphate binders (n = 1). While several of these studies were able to demonstrate reductions in hard cardiovascular endpoints such as myocardial infarction, survival improvement in ESRD patients was demonstrated in only three studies. The substances tested in these three trials were telmisartan, candesartan and carvedilol. In summary, most pharmaceutical mono-interventions failed to reduce mortality in ESRD patients, i.e. a multi-morbid population. Apart from the issues relating to future trial design, this raises the question of whether we need multi-faceted interventions to improve this dismal situation. Until then, nephrologists are left with little evidence and lots of opinions.