Chromosomal abnormalities are the most common alterations in acute myeloid leukemia (AML). Among those abnormalities, chromosomal translocations that produce the oncogenic fusion proteins have been frequently observed in different subtypes of AML. Although molecular mechanisms underlying the consequences of the oncogenic transformation resulted from the fusion proteins have been extensively studied, little is known about the molecular events cooperative with the oncogenic fusion proteins in the pathogenesis of leukemia and the cellular mechanisms with regard to the predictive roles of the fusions in treatment response. In this article, we will present an overview of the important aspects of AML-associated fusion proteins and their regulated transcriptional networks in pathogenesis and prognosis of AML. We will also discuss the recent findings pertaining to the functional link between the oncogenic fusions and response of leukemic cells to the treatment. Understanding the regulation of AML-associated fusions and their association with disease characteristics, patient outcome and treatment response will be of fundamental importance for predicting the effectiveness of the treatment and design the specific therapeutic strategies.