The causation of cancer, whether exogenous or endogenous, is a cornerstone of cancer prevention and treatment. Many intrinsic factors are discussed in other chapters of this book; this chapter will shed light on exogenous factors influencing cancer with detailed specific examples of microbial, physical and chemical factors. Microbial role in cancer has been debated over many centuries, whether as an antagonist or a cause, since Imhotep’s time through the mid-17th century when cancer was considered contagious, and later cancer hospitals were forcefully moved out of the cities as isolation camps. There are now vivid evidences that specific microbial pathogens are causing up to 25% of cancer cases (lymphoma, solid or others), and in some cases, a single pathogen was found in association with many types of cancer, such as HPV and EBV, to a lesser extent. Also, several non-biological factors are classified as carcinogens as humans are exposed to millions of chemicals whether in environment or smoke processed food.