Development of cancer therapeutics has traditionally focused on targeting driver oncogenes. Such an approach is limited by toxicity to normal tissues and treatment resistance. A class of 'cancer fitness genes' with crucial roles in metastasis have been identified. Elevated or altered activities of these genes do not directly cause cancer; instead, they relieve the stresses that tumor cells encounter and help them adapt to a changing microenvironment, thus facilitating tumor progression and metastasis. Importantly, as normal cells do not experience high levels of stress under physiological conditions, targeting cancer fitness genes is less likely to cause toxicity to noncancerous tissues. Here, we summarize the key features and function of cancer fitness genes and discuss their therapeutic potential.