Active cellular motility is required for tumor cell penetration of the basement membrane and the interstitial stroma during the transition from in situ to invasive carcinoma. Multiple factors, both autocrine and paracrine in origin, appear to influence this motile response. Recently, a potent new cytokine with molecular mass 120 kDa has been purified to homogeneity from a human melanoma cell line (A2058). This new protein, termed autotaxin (ATX), is a basic glycoprotein with pI approximately 7.7. ATX is active in the picomolar range, stimulating pertussis toxin sensitive chemotactic and chemokinetic responses by the same cell line that produces it. Sequence information, obtained on 11 purified tryptic peptides (114 residues), confirmed that the protein is unique with no significant homology to growth factors or previously described motility factors. It is hypothesized that an autocrine motility factor, such as ATX, could play a role in the initiation of the metastatic cascade by stimulating tumor cells to move away from the primary tumor. Other motility stimulating factors, such as components of the extracellular matrix or growth factors, could then influence both the time course and the localization of tumor cell spread.