Migration stimulating factor (MSF) is an oncofetal protein which is constitutively produced by both epithelial and stromal cells during fetal development, not expressed by the majority of their normal adult counterparts, but re-expressed during pathological processes such as cancer and wound healing. MSF exhibits a number of potent bioactivities, including the stimulation of cell migration, hyaluronan (HA) synthesis and angiogenesis. HA appears to mediate the effects of MSF on the migration of certain target cell types and may also contribute to the observed effects of MSF on angiogenesis. MSF expression and its precise effects on target cells are both subject to contextual (tissue-level) control mechanisms involving the complex interplay of soluble factors, such as TGFß1, and macromolecular constituents of the extracellular matrix, such as HA. Using MSF as an exemplar, we have suggested an “extended” oncofetal model of cancer pathogenesis in which epigenetic mechanisms make important contributions to the local and systemic re-expression of oncofetal molecules during disease progression. Critically, we propose that such oncofetal effectors may act as severity factors accelerating the disease process. Should this prove to be the case, the ability to switch-off inappropriate MSF expression may provide a platform for the development of novel adjuvant therapies designed to lower the risk of disease recurrence and mortality.