Objective Chemotherapy-induced thrombocytopenia (CIT) is a dose-limiting toxicity that can necessitate chemotherapy delays or dose reductions. This review examines evidence that CIT involves injury to both megakaryocytes (MKs) and the bone marrow microenvironment (BMME) and considers the implications for thrombopoietin receptor agonist (TPO-RA) therapy. Methods PubMed was searched for English-language literature without a publication-date restriction and was comprehensively updated through August 10, 2026. Evidence concerning CIT mechanisms and the mechanistic effects of TPO-RAs was integrated through a predefined narrative thematic framework, with explicit consideration of the directness of evidence for human CIT. Results Available studies suggest that TPO-RAs may have effects beyond platelet production, although evidence for vascular, metabolic, and immune microenvironmental effects derives largely from non-CIT or preclinical settings. Persistent rather than nadir CIT, lower endogenous thrombopoietin, and the absence of marrow infiltration, prior pelvic irradiation, or temozolomide exposure may enrich for response. A 2026 phase 3 trial directly demonstrated that romiplostim reduced CIT-induced chemotherapy dose modifications in persistent CIT, but biomarker-guided selection remains to be validated. Conclusion The “seed and soil” model organizes previously published evidence and should be regarded as hypothesis-generating in human CIT. Prospective studies are needed before microenvironment-directed combinations or CIT-specific biomarker thresholds can be recommended.