Chronic myeloid leukemia (CML) has been a “model disease” with a long history. Beginning with the first discovery of leukemia and the description of the Philadelphia Chromosome and ending with the current goal of achieving treatment-free remission after targeted therapies, we describe here the journey of CML, focusing on molecular pathways relating to signaling, metabolism and the bone marrow microenvironment. We highlight current strategies for combination therapies aimed at eradicating the CML stem cell; hopefully the final destination of this long voyage.