Simple Summary: The present review summarizes and interprets uniform therapy schemes for rescuing relapsed or refractory (r/r) neoplasias of quite different histologic origins. Exploiting tumor tissues' plasticity by reprogramming hallmarks of cancer into biologic hallmarks controlling tumor regrowth with metronomic chemotherapy and simultaneous targeting of nuclear and/or cytokine receptors plus/minus targeted therapies, termed tumor tissue editing, may induce cCR or long-term tumor control, as indicated by data from clinical trials designed for the treatment of r/r neoplasias of quite different histologic origins. Tumor tissue editing may overcome unique post-therapy disease traits that arise following treatment of r/r tumor disease with standard therapy regimens using maximum tolerable doses, i.e., metastatic spread, cancer repopulation, and acquired tumor cell resistance (M-CRAC), by attenuating, or resolving M-CRAC. The introduction of M-CRAC control in future therapeutic considerations may help to overcome the multifold translational challenges of precision medicine in the large group of r/r neoplasias without driver mutations. The concept of post-therapy metastatic spread, cancer repopulation and acquired tumor cell resistance (M-CRAC) rationalizes tumor progression because of tumor cell heterogeneity arising from post-therapy genetic damage and subsequent tissue repair mechanisms. Therapeutic strategies designed to specifically address M-CRAC involve tissue editing approaches, such as low-dose metronomic chemotherapy and the use of transcriptional modulators with or without targeted therapies. Notably, tumor tissue editing holds the potential to treat patients, who are refractory to or relapsing (r/r) after conventional chemotherapy, which is usually based on administering a maximum tolerable dose of a cytostatic drugs. Clinical trials enrolling patients with r/r malignancies, e.g., non-small cell lung cancer, Hodgkin's lymphoma, Langerhans cell histiocytosis and acute myelocytic leukemia, indicate that tissue editing approaches could yield tangible clinical benefit. In contrast to conventional chemotherapy or state-of-the-art precision medicine, tissue editing employs a multi-pronged approach targeting important drivers of M-CRAC across various tumor entities, thereby, simultaneously engaging tumor cell differentiation, immunomodulation, and inflammation control. In this review, we highlight the M-CRAC concept as a major factor in resistance to conventional cancer therapies and discusses tissue editing as a potential treatment. [ABSTRACT FROM AUTHOR]