Resistance to anticancer drugs is a major impediment to treating patients with cancer. The molecular mechanisms deciding whether a tumor cell commits to cell death or survives under chemotherapy are complex. Mounting evidence indicates a critical role of cell death and survival pathways in determining the response of human cancers to chemotherapy. Nuclear factor-kappaB (NF-kappaB) is a eukaryotic transcription factor on the crossroad of a cell's decision to live or die. Under physiological conditions, NF-kappaB is regulated by a complex network of endogenous pathway modulators. Tumor necrosis factor alpha induced protein 3 (tnfaip3), a gene encoding the A20 protein, is one of the cell's own inhibitory molecule, which regulates canonical NF-kappaB activation by interacting with upstream signaling pathway components. Interestingly, A20 is also itself a NF-kappaB dependent gene, that has been shown to also exert cell-type specific anti- or pro-apoptotic functions. Recent reports suggest that A20 expression is increased in a number of solid human tumors. This likely contributes to both carcinogenesis and response to chemotherapy. These data uncover the complexities of the mechanisms involved in A20's impact on tumor development and response to treatment, highlighting tumor and drug-type specific outcomes. While A20-targeted therapies may certainly add to the chemotherapeutic armamentarium, better understanding of A20 regulation, molecular targets and function(s) in every single tumor and in response to any given drug is required prior to any clinical implementation. Current renewed appreciation of the unique molecular signature of each tumor holds promise for personalized chemotherapeutic regimen hopefully comprising specific A20-targeting agents i.e., both inhibitors and enhancers.