Background: The War on Cancer has failed, due in part to its reliance on reductionist thinking to understand how cancer arises and evolves.

Methods: We reviewed cancer risk factors across major sites and categorized them based on a complexity theory approach of analyzing patterns of network behavior, which are more uniform than changes to downstream oncogenes. Focusing too much on specific details of the networks ignores the overriding theme that the emergence of generic network features is independent of these details.

Results: Cancer is caused by 9 sources of chronic cellular stress which often interact to provide the multiple “hits” that produce malignancy. They are: chronic inflammation (due to infection, infestation, autoimmune disorders, trauma, overweight, diabetes and other causes); exposure to carcinogens; reproductive hormones; Western diet (low fiber, vegetable and fruit consumption; high fat); aging; radiation; immune system dysfunction; germ line changes and random chronic stress / bad luck.

Conclusions: Cancer is an inevitable tradeoff of human biologic design that will always be with us, particularly as life expectancy increases. However, we can often prevent it, we can detect it earlier and we can treat it more effectively. Most cancer is cause by chronic cellular stress, which disturbs the delicate balance of our interconnected biologic networks. Malignancy arises due to a build up of hierarchies, in which combination of agents (biomarkers and networks) at one level become agents at the next level. Hierarchies are identifiable by patterns of molecular changes and sometimes by accompanying histologic changes. New cancer treatment approaches will focus on targeting multiple networks to overcome tumor heterogeneity, reducing the chronic stressors, moving networks into less lethal states and targeting the chaotic nature of tumors.