A hemodialysis system includes: (i) a dialyzer; (ii) a dialysate source; a dialysate pump; (iii) a dialysate cassette operatively connected to the dialysate pump such that the dialysate pump can pump dialysate through the dialysate cassette when the dialysate cassette is in fluid communication with the dialysate source, the dialysate cassette in fluid communication with the dialyzer; (iv) a blood pump; and (v) a blood cassette separate from the dialysate cassette, the blood cassette operatively connected to the blood pump such that the blood pump can pump blood through the blood cassette, the blood cassette including a housing, the housing including a from-patient tube connector, a to-patient tube connector, a saline/priming tube connnector, a to-dialyzer tube connector, a from-dialyzer tube connector, and an internal air separation chamber.