There is a global ESRD pandemic. Despite all therapeutic maneuvers and advances in dialysis care over the last two decades, ESRD patients on hemodialysis continue to experience high all-cause and cardiovascular mortality, with annual mortality rates exceeding 20%. There have been attempts to show that combination angiotensin converting enzyme inhibition and angiotensin receptor blockade therapy will help resolve this overwhelming cardiovascular mortality among hemodialysis patients. We present here, a balanced review of current knowledge on the benefits and pitfalls of the use of combination angiotensin converting enzyme inhibition and angiotensin receptor blockade in this vulnerable patient population. We conclude that there is no quick simple fix to the high cardiovascular mortality in hemodialysis patients. Combination angiotensin converting enzyme inhibition and angiotensin receptor blockade has not and will not solve the quagmire. Cardiovascular mortality among hemodialysis patients, clearly very high, is under the influence of just too many confounding factors and variables. Thus, in our mind, only through a concerted multifaceted approach, targeting all the variables discussed in this review, and more, and most importantly, with significant flexibility to individualize and tailor therapies as they are applicable and tolerated by specific individual patients, would we even begin to dent the high cardiovascular mortality among hemodialysis patients. A simple randomized placebo-controlled trial, just targeting one plausible etiologic factor, in our opinion, will hardly prove any more useful than previous such trials have demonstrated in the past.