It is now clear that platelets have a functionally important role in many aspects of cancer biology. Here, we examine the evolutionary connections that position platelets at the intersection of hemostasis, immunity, and adaptive phylogeny—all integral to normal wound healing and immune surveillance, which can be coopted by cancer cells to influence cancer growth and metastasis. Unlike thrombocytes and platelets found in lower vertebrates, mammalian and marsupial platelets are anucleate. Genesis adaptations also occurred to meet the significant production and replacement demands during menses and parturition. Billions of platelets are generated and recycled each day to maintain homeostasis, providing a robust defense and adaptability against evolving microbial threats and cancer cells. This process is driven by megakaryocytes, the largest cells in the body, which shed anuclear membranous cytoplasmic fragments into the bone marrow’s cavities and subsequently into the circulation, all within a protective bone encased microenvironment. Due to their small size, platelets are often difficult to detect using standard pathological methods, and any changes in their behavior are best observed through electron microscopy. Their biophysical properties became more plate-like in morphology, which contributes to their intravascular distribution and functions. This evolution facilitated better distribution near vessel walls within fluid-shear fields, consequently increasing the probability that platelets would react to gaps in the endothelial monolayers lining the vascular lumen. They retained an active cytoskeleton that drives dramatic shape change and motility that leads to their fading histologically into the surrounding tissue milieux as they transform into aggregates that immobilize pathogens and circulating cancer cells. Moreover, human platelets express numerous receptors that bind foreign entities, evolving from archetypal origins to initiate the aggregation and exocytic release of granule contents that initiate thrombo-, immuno-, angiogenic-, growth-, and repair-stimulatory functions. These responses—whether shaped by direct evolutionary selective pressure or not—can help contain the spread of pathogens, attract immune cells for the eradication of pathogens, and promote angiogenesis, growth, and wound repair following tissue damage or tumor growth. Additionally, platelets generate circulating microvesicles that increase the surface area for encounters and target circulating tumor cells. They also exhibit “education capabilities” as they traverse growing tumors. However, the role of platelets as integral components of the immune response, as well as in cancer immunobiology and metastasis, remains less well-explored compared to other functions. The current focus on cancer subtype identification and patient molecular profiling, primarily through RNA and DNA sequencing, often overlooks platelet involvement, highlighting a significant gap in our understanding. This knowledge gap likely extends to the recent advances in immune surveillance, checkpoint blockade, immune therapy, and the emerging understanding of the significant influence of the microbiome in cancer and metastasis and immunotherapy responses.