Steroid receptor coactivator 3 (SRC-3/AIB1/ACTR/RAC3/p/CIP), a member of the p160 family of coactivators, is a bona fide oncogene involved in many human cancers. Development of cancer is a multistep process that requires changes of intrinsic cellular functions and interaction of cancerous cells with the tumor microenvironment. Cancer cells are “addicted” to SRC-3/AIB1 oncogene as over-expression of SRC-3/AIB1 is found in many human cancers and is associated with cancer initiation, metastasis and resistance to chemotherapy. However, the reason why cancer cells are addicted to SRC-3/AIB1 oncogene remains unclear. Therefore, understanding the molecular mechanisms underpinning the oncogenic activity of SRC-3/AIB1 is critical for improving anti-cancer therapy. To fully understand the mechanisms by which SRC-3/AIB1 contributes to the development and progression of human cancer, we had identified several molecular targets of SRC-3/AIB1 by functional rescue experiments and gene expression profiling. Currently, we are focusing on understanding the function and importance of these molecular targets of SRC-3/AIB1 in tumorigenesis and on elucidating the underlying mechanisms at the molecular and cellular levels. Since most current targeted cancer therapies are designed to block a single pathway, cancers often become resistant by switching to another growth pathway. In contrast, cancer cells are less likely to survive loss of SRC-3/AIB1 oncogene because of this “addiction”. Since SRC-3/AIB1 is frequently over-expressed in a wide variety of cancers, our study also argues that cancer drugs targeting SRC-3/AIB1 is likely to impact more than one type of cancer.