Despite major research efforts and improvements in dialysis technology, patients with end-stage renal disease (ESRD) experience an extremely high mortality, which seems to be increasingly related to cardiovascular disease. Cardiovascular disease has been linked to the presence of systemic inflammation and malnutrition (MIA syndrome), in addition to the high prevalence of traditional risk factors observed in ESRD patients. Since the mechanisms underlying the development of these complications of ESRD are largely unknown, new strategies for identification of risk factors, pathophysiologic pathways, and targets for intervention are warranted. Although the combined impact of MIA complications seems to determine the extremely poor clinical outcome in the ESRD patients, there are significant unexplained individual differences in the development of the MIA syndrome, implying that genetic differences might play a role. The vast information generated by the advances in molecular genetics offers a great opportunity to analyze the causes of differences not only in our susceptibility to (or protection from) various diseases, but also in the age of onset, severity of illness, and in the way our bodies respond to treatment. In this review, we summarize an integrated approach in the investigation of complex disorders, requiring the interactive collaboration between laboratory, clinical, and epidemiologic resources using the MIA syndrome as a prototype. We focus on the application of common genetic variations (single nucleotide polymorphisms [SNPs]) in association with studies to generate potential risk profiling using data from multiple vulnerability genes. The appropriate application of this approach may be essential in the early identification of high-risk individuals and groups of patients for whom specific therapeutic interventions are indicated, thus creating a tailor-made clinical management for the future.