An aneurysm of the abdominal aorta is a common pathology and a major cause of sudden death in the elderly. Currently, abdominal aortic aneurysms (AAAs) can only be treated by surgery and an effective medical therapy is urgently missing. The pathophysiology of AAAs is complex and is believed to be best described as a comprehensive inflammatory response with an accompanying proteolytic imbalance; the latter being held responsible for the progressive weakening of the aortic wall. Remarkably, while interference in inflammatory and/or proteolytic cascades proves highly effective in preclinical studies, emerging clinical studies consistently fail to show a benefit. In fact, some anti-inflammatory interventions appear to adversely influence the disease process. Altogether, recent clinical observations not only challenge the prevailing concepts of AAA progression, but also raise doubt on the translatability of findings from rodent models for growing AAA.