Acute myeloid leukemia (AML) is a cancer of blood and bone marrow, caused by abnormal production of white blood cells. According to the recent 2020 statistics, an estimated number of 19,940 people in the United States will be diagnosed with AML. The hematologic tumor microenvironment plays a critical role in the progression of AML. Emerging evidence indicates that chemotherapy resistance and disease relapse are linked through the signaling pathways associated with the tumor microenvironment in AML. The leukemia cells communicate with the other noncancerous cells of the tumor microenvironment through small vesicles that are within the size of 30-120nm called exosomes, a type of extracellular vesicles. Exosomes contain genetic information in their cargo, in the form of either protein, DNA, or noncoding RNAs and communicate to the distinct cells through various signaling pathways. The c-Myc oncogenic transcription factor protein is a master regulator of oncogenic signaling pathways in various cancers, including AML. C-Myc has been associated with the development of therapy resistance in AML, representing a key target. The interconnection between exosomes, tumor microenvironment, c-Myc and the development of progression, therapy resistance are discussed in this chapter and thus, represents a fundamental knowledge of the recent advances in cancer signal transduction and therapy.