Background: Osteosarcoma is the most common bone tumor in children and adolescents. Despite multiagent chemotherapy, only 71% of patients survives and these survivors often experience long-term toxicities. The main objective of this systematic review is to provide an overview of the discovery of novel associations of germline polymorphisms with treatment response and/or chemotherapy-induced toxicities in osteosarcoma.Methods: MEDLINE and Embase were systematically searched (2010-2020). Genetic association studies were included if they assessed >10 germline genetic variants in > 5 genes in relevant drug pathways or if they used a genotyping array or other large-scale genetic analysis. Quality was assessed using adjusted STrengthening the REporting of Genetic Association studies (STREGA)-guidelines. To find additional evidence for the identified associations, literature was searched to identify replication studies.Results: After screening 1533 articles, fifteen articles met our inclusion criteria. These range from studies focusing on genes in relevant pharmacokinetic pathways to whole genome sequencing. Eight articles reported on doxorubicin-induced cardiomyopathy. For seven genetic variants in CELF4, GPR35, HAS3, RARG, SLC22A17, SLC22A7 and SLC28A3, replication studies were performed, however without consistent results. Four small studies reported on bone marrow, nephro- and/or hepatotoxicity. Six studies included analysis for treatment efficacy. Genetic variants in ABCC3, ABCC5, FasL, GLDC, GSTP1 were replicated in studies using heterogeneous efficacy outcomes.Conclusions: Despite that results are promising, the majority of associations were poorly reproducible due to small patient cohorts. For the future, hypothesis-generating studies in large patient cohorts will be necessary, especially for cisplatin-induced ototoxicity as these are lacking. In order to form large patient cohorts, national and international collaboration will be essential.