Introduction: The search for the 'perfect' renal replacement therapy has been paralleled by the search for the perfect biomarkers for assessing dialysis adequacy. Three main families of markers have been assessed: small molecules (prototype: urea); middle molecules (prototype β2-microglobulin); comprehensive and nutritional markers (prototype of the simplified assessment, albumin levels; composite indexes as malnutrition-inflammation score). After an era of standardization of dialysis treatment, personalized dialysis schedules are increasingly proposed, challenging the dogma of thrice-weekly hemodialysis. Areas covered: In this review, we describe the advantages and limitations of the approaches mentioned above, focusing on the open questions regarding personalized schedules and incremental hemodialysis. Expert opinion: In the era of personalized dialysis, the assessment of dialysis adequacy should be likewise personalized, due to the limits of 'one size fits all' approaches. We have tried to summarize some of the relevant issues regarding the determination of dialysis adequacy, attempting to adapt them to an elderly, highly comorbidity population, which would probably benefit from tailor-made dialysis prescriptions. While no single biomarker allows precisely tailoring the dialysis dose, we suggest using a combination of clinical and biological markers to prescribe dialysis according to comorbidity, life expectancy, residual kidney function, and small and medium-size molecule depuration.