Metastasis is a late stage of malignant cancer. However, recent evidence suggests that mutations contributing to metastasis may be acquired by cancer cells at much earlier stage. This has been referred to as the cancer progression puzzle. Phospholipase D (PLD) is a ubiquitous enzyme that hydrolyzes phosphatidylcholine to produce phosphatidic acid (PA) and choline where PA is considered to be the critical lipid second messenger. Both PLD expression level and enzymatic activity are elevated in variety of human cancers. We have shown that, under the stress condition of serum withdrawal, PLD activity is elevated and provides a survival signal in the human breast cancer cell line MDA-MB-231, likely to be critical early in the tumor progression, to suppress default apoptotic programs. Of the significance, we also found that the elevated PLD activity enhances the invasive behavior of MDA-MB-231 cells, thus linking the early survival advantage with later metastatic potential. Serum reduction in culture is similar to the conditions endured by early stage cancer cells in an unvascularized solid tumor, where there is a lack of growth factors and nutrients. Under such conditions, we hypothesize that some cancer cells respond by elevating their PLD activity. These cells would have a better chance at not only surviving, but also migrating to new sites and forming new colonies where blood supply is available. Further mutations among the population of these colonies would further advance progression to malignant cancer. This hypothesis provides a possible answer to the cancer progression puzzle. We propose that some malignant cancers acquire at least part of the metastatic capability at an early stage of tumorigenesis, by selection for the survival of the emerging cancer cell, against the pressure of a poor blood supply in poorly vascularized tumors.