Cancer development and therapy resistance are driven by chromosomal instability (CIN), which causes chromosome gains and losses (i.e., aneuploidy) and structural chromosomal alterations. Technical limitations and knowledge gaps have delayed therapeutic targeting of CIN and aneuploidy in cancers. However, our toolbox for creating and studying aneuploidy in cell models has greatly expanded recently. Moreover, accumulating evidence suggests that seven conventional antimitotic chemotherapeutic drugs achieve clinical response by inducing CIN instead of mitotic arrest, although additional anticancer activities may also contribute in vivo. In this review, we discuss these recent developments. We also highlight new discoveries, which together show that 25 chromosome arm aneuploidies (CAAs) may be targetable by 36 drugs across 14 types of cancer. Collectively, these advances offer many new opportunities to improve cancer treatment.