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Importance Targeted alpha therapy attempts to deliver systemic radiation selectively to cancer cells while minimizing systemic toxic effects and may lead to additional treatment options for many cancer types. Observations Theoretically, the high-energy emission of short-range alpha particles causes complex double-stranded DNA breaks, eliciting cell death. No known resistance mechanism to alpha particles has been reported or scientifically established. The short-range emission of alpha particle radiation confines its cytotoxic effect to cancerous lesions and the surrounding tumor microenvironment while limiting toxic effects to noncancerous tissues. The high level of radiobiological effectiveness of alpha particles, in comparison with beta emissions, requires fewer particle tracks to induce cell death. Clinically effective alpha particle–emitting isotopes for cancer therapy should have a short half-life, which will limit long-term radiation exposure and allow for the production, preparation, and administration of these isotopes for clinical use and application. Radium 223 dichloride is the first-in-class, commercially available targeted alpha therapy approved for the treatment of patients with metastatic castration-resistant prostate cancer with bone metastases. Given the established overall survival benefit conferred by radium 223 for patients with metastatic castration-resistant prostate cancer, several other targeted alpha therapies are being investigated in clinical trials across many tumor types. Conclusions and Relevance Targeted alpha therapy represents an emerging treatment approach and provides for the possibility to bypass mechanisms of acquired resistance in selected tumors. In addition, developing novel radionuclide conjugation strategies may overcome targeting limitations. So far, the clinical success of radium 223 has demonstrated the proof of concept for targeted alpha therapy, and future studies may lead to additional treatment options for many cancer types.