Focal treatment with radiofrequency, microwave and cryoablation has been increasingly used for the treatment of tumors in patients who cannot undergo surgical resection and in select patients with early stage or oligometastatic disease. Each of these ablation modalities has a unique working principle and biophysics underlying the ablative effect, which largely determines the clinical indication for its application. Irreversible electroporation, a relatively new ablation technique with a predominantly nonthermal cell killing mechanism has emerged as an alternative treatment technique for tumors that are contraindicated for thermal ablation because of safety or efficacy considerations. Here, established thermal ablation techniques are compared with irreversible electroporation for treatment of tumors in the lung, liver, kidney and bone, and rationale is provided to guide selection of the most appropriate technique for each clinical setting.