Recently, 'super high-flux' (SHF) or 'high cut-off' (HCO) membranes have been developed to increase the clearance of inflammatory mediators. In the experimental and clinical settings, SHF/HCO membranes appear to achieve greater clearance of inflammatory cytokines than conventional high-flux membranes. SHF/HCO membranes also restore immune cell function, attenuate hemodynamic instability and decrease plasma IL-6 levels. Moreover, SHF/ HCO membranes can eliminate larger late-phase inflammatory mediators such as HMGB-1. Although albumin sieving coefficients with SHF/HCO membranes are greater than with conventional high-flux membranes, the daily amount lost is limited and can be replaced. Hemodialysis with SHF/HCO membranes can also achieve similar cytokine removal to hemofiltration with acceptable albumin losses. When strategies for sepsis or systemic inflammation treatment target middle molecular mediators, both SHF/HCO hemofiltration and hemodialysis appear feasible and safe and require further clinical investigation.