Cancer is a leading global cause of death, with projections estimating 16.4 million deaths annually by 2040. The complexity of cancer, driven by both internal and external factors, necessitates innovative research focused on prevention, early detection, and personalized treatments. Natural products, especially those from plants, environments, and microorganisms, have been crucial in developing anticancer drugs, with over 60% of current treatments derived from these sources. Recent efforts have intensified in identifying bioactive compounds from microbes due to increasing cancer cell resistance to conventional treatments and severe side effects. Microbes, with their vast species diversity, produce a wide range of bioactive products that are often more cost-effective to extract than to synthesize chemically. These microbial agents can modulate the immune response, inhibit cell division, and induce apoptosis, offering potential solutions to multidrug resistance and toxicity issues. Microorganisms, particularly those from extreme environments, are rich sources of unique anticancer metabolites. Understanding the mechanisms by which microbial-derived agents exert anticancer effects—such as inhibiting signaling pathways, inducing necrosis and apoptosis, reducing angiogenesis, and interfering with translation and splicing—is essential for their therapeutic application. This chapter explores the diverse categories of microbial-derived anticancer compounds, their mechanisms of action, practical applications, and the challenges they face. It highlights recent advancements and promising outcomes in translating these compounds from laboratory research to clinical use, emphasizing their significant potential to improve cancer treatment outcomes.