A bioterrorism attack would be particularly challenging for medical professionals caring for patients with cancer who often have weakened immune systems. Knowledge of the class A agents and the potential variable presentations in immunocompromised patients is key to early recognition of an outbreak and prompt reporting. The purpose of this article is to present the class A agents: Bacillus anthracis (anthrax), botulinum toxin (botulism), variola virus (smallpox), Yersinia pestis (pneumonic plague), and Francisella tularensis (tularemia). The variable signs and symptoms that may be present in immunocompromised patients with cancer will be discussed with a focus on assessment and early recognition of an outbreak. The availability of vaccines and the implications for patients with cancer receiving these vaccines also will be discussed.