Prognosis of myelodysplastic syndromes (MDS) is based on scoring systems focusing on disease-related factors; however, several studies have shown that patient-related factors might be equally important in prognostication of patients with malignancies in general but also for patients with MDS. The aim of this review was to evaluate the role of comorbidities and frailty as prognostic factors as well as predictive factors of response and tolerability to hypomethylating agents. Both comorbidities and frailty were shown to be predictive of overall survival; however, they mostly correlate with risk for non-leukemic death rather than leukemia-free survival. In patients with higher-risk MDS, comorbidities burden and frailty might be predictive of poor treatment response as well as increased toxicity. In this context, all patients with MDS should be evaluated for comorbidities and frailty at baseline, preferentially using indices validated for MDS. This assessment should guide the selection of treatment. Decision regarding treatment initiation should be based on disease-related factors as captured by the established prognostic scoring systems. •Comorbidities and frailty impact overall survival of patients with MDS and are associated with an increased risk of non-leukemic death.•Comorbidities and frailty might predict response to treatment with hypomethylating agents.•Patients with increased comorbidities and frailty demonstrate increased toxicity and adverse events to hypomethylating agents.•Comorbidities and frailty should be assessed in all patients as to guide selection of treatment.•Decision for treatment onset should be based on the established prognostic scoring systems.