Despite improved survival outcomes across many cancer types, the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer. Invariably in these cancers, the control achieved by time-limited interventions such as traditional surgical resection, radiation therapy, and chemotherapy is short-lived. A new form of anti-cancer therapy called therapeutic alternating electric fields (AEFs) or tumor treating fields (TTFields) has been shown, either by itself or in combination with chemotherapy, to have anti-cancer effects that translate to improved survival outcomes in patients. Although the pre-clinical and clinical data are promising, the mechanisms of TTFields are not fully elucidated. Many investigations are underway to better understand how and why TTFields is able to selectively kill cancer cells and impede their proliferation. The purpose of this review is to summarize and discuss the reported mechanisms of action of TTFields from pre-clinical studies (both in vitro and in vivo). An improved understanding of how TTFields works will guide strategies focused on the timing and combination of TTFields with other therapies, to further improve survival outcomes in patients with solid organ cancers.