Phosphorus, often in the form of inorganic phosphate (Pi), is critical to cellular function on many levels; it is required as an integral component of kinase signaling, in the formation and function of DNA and lipids, and energy metabolism in the form of ATP. Accordingly, crucial aspects of cell mitosis – such as DNA synthesis and ATP energy generation – elevate the cellular requirement for Pi, with rapidly dividing cells consuming increased levels. Mechanisms to sense, respond, acquire, accumulate, and potentially seek Pi have evolved to support highly proliferative cellular states such as injury and malignant transformation. As such, manipulating Pi availability to target rapidly dividing cells presents a novel strategy to reduce or prevent unrestrained cell growth. Currently, limited knowledge exists regarding how modulating Pi consumption by pre-cancerous cells might influence the initiation of aberrant growth during malignant transformation, and if reducing the bioavailability or suppressing Pi consumption by malignant cells could alter tumorigenesis. The concept of targeting Pi-regulated pathways and/or consumption by pre-cancerous or tumor cells represents a novel approach to cancer prevention and control, although current data remains insufficient as to rigorously assess the therapeutic value and physiological relevance of this strategy. With this review, we present a critical evaluation of the paradox of how an element critical to essential cellular functions can, when available in excess, influence and promote a cancer phenotype. Further, we conjecture how Pi manipulation could be utilized as a therapeutic intervention, either systemically or at the cell level, to ultimately suppress or treat cancer initiation and/or progression.