The bone marrow microenvironment provides a site for cancer cells to evade systemic anticancer therapy. Dormant tumor micrometastases are believed to be the source of disease persistence and relapse; however, the exact characteristics of cancer stem cells vs. cancer cells with limited metastatic potential have yet to be elucidated. Bisphosphonates inhibit osteoclast-mediated bone resorption, are approved for treating malignant bone disease from advanced cancers, and have shown efficacy for preventing cancer treatment-induced bone loss. Altering the bone marrow microenvironment to make it less conducive to cancer cell survival is now emerging as an important means to prevent cancer recurrence. This review aims to distill the diverse literature and provide a brief overview of the numerous preclinical and early clinical studies of bisphosphonates demonstrating a variety of direct and indirect anticancer activities that affect both the tumor cell (the “seed”) and surrounding microenvironment (the “soil”). Recently, zoledronic acid was found to improve disease-free survival and overall survival in some adjuvant breast cancer settings and prolonged survival in patients with multiple myeloma and other advanced cancers. In the prostate cancer setting, antiresorptive therapy was reported to delay the development of overt bone metastases. Ongoing studies will provide further insight regarding the anticancer potential of bisphosphonates and other antiresorptive agents.