The typical dialysis patient faces both a poor quality of life and a significantly shortened survival. This is often blamed on "uremia." However, defining the clinical entity of uremia is surprisingly difficult. It represents the clinical sequelae of the effects of retention products, other effects of renal disease, and the effects of other comorbid conditions. The list of retention products that could act as uremic toxins is lengthy, but it would appear that urea itself does not contribute significantly to the uremic state. Larger molecular weight substances are likely the major contributors to the uremic milieu. Regardless of the causes, the uremic state persists in many patients who are reaching their dialysis adequacy targets as defined by urea clearance. This raises the possibility that more intensive hemodialysis could improve patient outcomes. Hemodialysis can be intensified by increasing dialysis efficiency without changing duration or frequency. Alternatively, hemodialysis duration, frequency, or both can be increased. All intensification methods increase small solute removal, but the removal of larger molecular weight retention products depends more upon treatment time. Modalities such as short daily hemodialysis, long intermittent hemodialysis, and quotidian nocturnal hemodialysis have been associated with a variety of clinical improvements, as well as improvements in quality of life and a lower standardized mortality ratio. However, the HEMO study approach of intensifying small solute clearance without significant modifications of the dialysis schedule does not appear to be effective. Future research will help to define the optimal treatment duration and frequency in hemodialysis patients.