Protein degradation is a key cellular process involved in almost every aspect of the living cell. The current prevailing concept is that proteins are stable unless marked by poly-ubiquitination for degradation by the proteasomes. Studies on the tumor suppressor p53 have indeed demonstrated that poly-ubiquitination of p53 by different E3 ubiquin ligases targets p53 for degradation by the 26S proteasomes. Recent findings suggest that p53 also undergoes ubiquitin-independent degradation by the 20S proteasomes and that this process is regulated by NAD(P)H quinone oxidoreductase 1 (NQO1) together with NADH. This "degradation by default" mechanism sheds new light on our understanding of p53 degradation and possibly on protein degradation in general and may establish a new principle in protein stability with wide physiological implications.