Adenoviruses (Ads) are arguably one of the most potent viruses for in vivo gene therapy, vaccine, and oncolytic applications. The attraction for the use of Ads stems from their ability to infect a wide range of dividing and non-dividing cell types in some cases to efficiencies of nearly 100%. Additional benefits include their stability, the ability to purify the vector to concentrations of up to 1013 particles/ml, and the fact that viral vectors self-assemble into particles of specific size (∼100 nm). The vast majority of clinical applications of Ad have utilized Ad serotype 5 (Ad5) viruses. Considering that at least half of humans are already immune to Ad5, Ad5 oncolytics may not be optimal for clinical translation. Given this and that there are 54 different serotypes of human Ads, this review considers the utility of "mining" these alternate Ad serotypes for viruses that can evade Ad5 immunity and kill different types of cancer.