Although it is generally accepted that aging increases postoperative morbidity and mortality rates, the underlying mechanism remains unknown. The present review evaluates the clinical implications of remodeling the immunoinflammatory status with reference to inflammaging and tumor-specific hyperinflammation. We conducted a Medline/PubMed search for articles investigating factors related to aging and their effects on postoperative outcomes. Inflamm-aging results in both decreased immunity to exogenous antigens and increased auto-reactivity, whereby the beneficial effects of inflammation devoted to the neutralization of harmful agents early in life become detrimental late in life. Cancer also represents an immunologic challenge, which upregulates the systemic immune response. Thus, tumor-related hyperinflammation and inflamm-aging synergistically lead to the systemic priming of inflammatory mediators preoperatively; then, surgical stress acts as the second hit, increasing the risk of an exaggerated postoperative inflammatory response. Age-related molecular events may place elderly patients at greater risk of postoperative complications which could result in death. For regulating uncontrolled hyperinflammation, the clinical advantages of perioperative immunonutrition or steroids have been advocated; however, double-blind, randomized, controlled trials of pharmacologic modulation therapy are needed.