Observational studies in chronic kidney disease (CKD) populations consistently have shown the strong mortality-predictability of such markers of protein-energy wasting (PEW) as hypoalbuminemia, low serum cholesterol levels, low body mass index, and reduced dietary protein intake. Even though the PEW-mortality association data traditionally are reported mostly in maintenance dialysis patients, emerging studies extend the existence of these associations to predialysis stages of CKD. Paradoxic risk factor patterns (reverse epidemiology) for both obesity and cholesterol recently have been reported in predialysis CKD, underscoring the overwhelming impact of PEW, a short-term killer, on reversing the long-term effect of conventional cardiovascular risk factors. Multiple pathophysiologic mechanisms have been suggested to explain the link between PEW and mortality in CKD, including derangements in muscle, adipose tissue, and the gastrointestinal, hematopoietic, and immune systems; complications related to deficiencies of multiple micronutrients; and the maladaptive activation of the inflammatory cascade. In addition to well-described pathophysiologic mechanisms involved in the higher mortality seen with PEW, we also discuss the potential role of novel factors such as circulating actin, gelsolin, and proinflammatory high-density lipoprotein. Whether PEW is causally related to adverse outcomes in CKD needs to be verified in randomized controlled trials of nutritional interventions. The initiation of major clinical trials targeting nutritional interventions with the goal of improving survival in CKD offer the promise of extending the survival of this vulnerable patient population.