Cancer is a complex collection of distinct genetic diseases united by common hallmarks. Here, we expand upon the classic hallmarks to include the stress phenotypes of tumorigenesis. We describe a conceptual framework of how oncogene and non-oncogene addictions contribute to these hallmarks and how they can be exploited through stress sensitization and stress overload to selectively kill cancer cells. In particular, we present evidence for a large class of non-oncogenes that are essential for cancer cell survival and present attractive drug targets. Finally, we discuss the path ahead to therapeutic discovery and provide theoretical considerations for combining orthogonal cancer therapies.