The liver is a common site for metastatic disease. In select patients with isolated liver metastases, surgical resection improves survival and may be potentially curative in patients with favorable “tumor biology”. However, when surgical resection is not feasible, liver-directed therapies (LDTs) can also improve outcomes, including survival, in the appropriate clinical situations. LDTs, including hepatic artery infusion, radioembolization, radiation, and ablation techniques, such as thermal ablation and histotripsy, offer local control and potential systemic effects, including the abscopal effect. The abscopal effect occurs when nontargeted, nontreated tumors regress following localized therapy to other tumors. Preclinical and clinical studies suggest that antigen-induced upregulation of key immune regulators plays a central role in this process. Unfortunately, clinical reports of the abscopal effect following LDT are exceedingly rare. However, histotripsy, a noninvasive, nonionizing, and nonthermal ablation technique, may induce an abscopal effect more frequently and robustly than other LDTs. Histotripsy enhances tumor immunogenicity through precise acoustic cavitation that better preserves the local tissue architecture while increasing antigen release, resulting in a robust local and systemic immune response. Ongoing trials are investigating these immunogenic mechanisms and the ability to generate an abscopal effect more reliably with adjuncts such as checkpoint inhibitors. This work has significant implications regarding the management of patients with liver metastasis.