The present invention provides systems, methods and apparatuses for medical fluid delivery systems that employ a pumping cassette. In particular, the present invention provides systems, methods and apparatuses for cassette-based dialysis therapies including hemodialysis, hemofiltration, APD (including tidal modalities) and CFPD. The embodiments described include a combined pump/valve housing, a fail safe pump/valve arrangement, a cassette auto-alignment feature, a pumping membrane material, a multiplexing valve arrangement, an expert fluid pumping management system, an integral port vent and an in-line air separation chamber and combinations of each of these.