Nanomedicine is a novel field of study that involves the use of nanomaterials to address challenges and issues that are associated with conventional therapeutics for cancer treatment including, but not limited to, low bioavailability, low water-solubility, narrow therapeutic window, nonspecific distribution, and multiple side effects of the drugs. Multiple strategies have been exploited to reduce the nonspecific distribution, and thus the side effect of the active pharmaceutical ingredients (API), including active and passive targeting strategies and externally controllable release of the therapeutic cargo. Site-specific release of the drug prevents it from impacting healthy cells, thereby significantly reducing side effects. API release triggers can be either externally applied, as in ultrasound-mediated activation, or induced by the tumor. To rationally design such nanomedicines, a thorough understanding of the differences between the tumor microenvironment versus that of healthy tissues must be paired with extensive knowledge of stimuli-responsive biomaterials. Herein, we describe the characteristics that differentiate tumor tissues from normal tissues. Then, we introduce smart materials that are commonly used for the development of smart nanomedicines to be triggered by stimuli such as changes in pH, temperature, and enzymatic activity. The most recent advances and their impact on the field of cancer therapy are further discussed.