It has been speculated for many years that heparanase plays an important role in the progression of cancer due largely to the finding that its expression is weak or absent in normal tissues but generally as tumors become more aggressive heparanase expression increases. However, it is only in the last decade or so that we have begun to understand the molecular mechanism behind the sinister role that heparanase plays in cancer. In this review, we describe the many functions of heparanase in promoting the growth, angiogenesis and metastasis of multiple myeloma, a devastating cancer that localizes predominantly within the bone marrow and spreads throughout the skeletal system devouring bone and ultimately leading to death of almost all patients diagnosed with this disease. We also explore recent discoveries related to how heparanase primes exosome biogenesis and how heparanase enhances myeloma tumor chemoresistance. Discovery of these multiple tumor-promoting pathways that are driven by heparanase identified the enzyme as an ideal target for therapy, an approach recently tested in a Phase I trial in myeloma patients.