Caloric restriction (CR) is an innovative therapy used in tumor tissue and tumor model studies to promote cell death and decrease cell viability. Caloric restriction mimetics (CRMs) are a class of drugs that induce CR and starvation conditions within a cell.When used simultaneously with other chemotherapy agents, the effects are synergistic and effective at promoting tumor cell death. In this review, we discuss CRMs and their potential as cancer therapeutics. Firstly, we establish an overview of CR and its impacts on healthy and tumor cells. CR and CRM drugs have shown to decrease age-related diseases and can act as an anti-cancer agent. As it can be challenging for an individual to diligently stick to a diet that would induce CR, CRMs are even more desirable. Then, we discuss the drug class by highlighting three CRMs: resveratrol, (-)-hydroxycitric acid, and rapamycin. These CRMs are commonly known for their dietary effects, but the underlying mechanisms that drive cellular metabolic and proteomic changes show promise as a cancer therapeutic. Lastly, we highlight the use of mass spectrometry and proteomic techniques on experiments utilizing CRM drugs to understand the cellular pathways impacted by this drug class, leading to a better understanding of the anticancer properties and potentials of CRM.