Since the initial discovery of AEG-1/MTDH/LYRIC, our appreciation for this novel protein's involvement in cancer has increased dramatically over the past few years. AEG-1/MTDH/LYRIC is a key functional target of the 8q22 genomic gain that is frequently observed in poor-prognosis breast cancer, where it plays a dual role in promoting chemoresistance and metastasis. Beyond this, growing evidence from clinical research indicates a strong correlation between AEG-1/MTDH/LYRIC expression and the pathogenesis of a large spectrum of cancer types, and multiple studies employing in vitro cell culture systems and in vivo xenograft models have revealed multifaceted roles of AEG-1/MTDH/LYRIC in cancer biology, including tumor cell proliferation, apoptosis, angiogenesis, and autophagy. With increasing mechanistic understanding of AEG-1/MTDH/LYRIC, discovery of agents that can block AEG-1/MTDH/LYRIC and its regulated pathways will be beneficial to cancer patients with aberrant expression of AEG-1/MTDH/LYRIC.