Cancer initiation and progression have been attributed to newly discovered subpopulations of self-renewing, highly tumorigenic, drug-resistant tumor cells termed cancer stem cells. Recently, we and others reported a new phenotypic plasticity wherein highly tumorigenic, drug-resistant cell populations could arise not only from pre-existing cancer stem-like populations but also from cancer cells lacking these properties. In the current study, we hypothesized that this newfound phenotypic plasticity may be mediated by PI3K/Akt and Wnt/β-catenin signaling, pathways previously implicated in carcinogenesis, pluripotency and drug resistance. These studies provide a mechanistic model wherein PI3K/Akt/beta-catenin/CBP signaling mediates phenotypic plasticity in and out of a drug-resistant, highly tumorigenic state. Therefore, targeting this pathway has unique potential for overcoming the therapy resistance and disease progression attributed to the cancer stem-like phenotype.