Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine.
Here, we review data and technologies that have revealed intra-tumor heterogeneity across cancer
types and the dynamics, constraints, and contingencies inherent to tumor evolution. We emphasize
the importance of macro-evolutionary leaps, often involving large-scale chromosomal alterations,
in driving tumor evolution and metastasis and consider the role of the tumor microenvironment in
engendering heterogeneity and drug resistance. We suggest that bold approaches to drug development,
harnessing the adaptive properties of the immune-microenvironment while limiting those
of the tumor, combined with advances in clinical trial-design, will improve patient outcome
