The results of clinical trials performed from the 1930s until the end of the 20th century in which total-body ultra-low level ionizing radiation (TB-LLR) was used demonstrate that this form of treatment can be equal or superior to other systemic anti-neoplastic modalities in terms of the rates of remissions, toxicity, and side effects. In this review, we provide the rationale for TB-LLR and analyze the results of reliable clinical trials in patients with predominantly lymphoproliferative disorders but also advanced solid cancers. The doses used in these trials did not exceed 0.1-0.2 Gy per fraction and cumulative totals ranged from 1 to 4 Gy. Based on the reviewed results we conclude that it is appropriate to revive interest in and resume clinical investigations of TB-LLR in order to refine and improve the effectiveness of such treatment, whether employed alone or in combination with other anticancer strategies.