Myeloid‐derived suppressor cells (MDSCs) are present in most cancer patients and experimental animals where they exert a profound immune suppression and are a significant obstacle to immunotherapy. IFN‐γ and IL‐4 receptor alpha (IL‐4Rα) have been implicated as essential molecules for MDSC development and immunosuppressive function. If IFN‐γ and IL‐4Rα are critical regulators of MDSCs, then they are potential targets for preventing MDSC accumulation or inhibiting MDSC function. Because data supporting a role for IFN‐γ and IL‐4Rα are not definitive, we have examined MDSCs induced in IFN‐γ‐deficient, IFN‐γR‐deficient, and IL‐4Rα‐deficient mice carrying three C57BL/6‐derived (B16 melanoma, MC38 colon carcinoma, and 3LL lung adenocarcinoma), and three BALB/c‐derived (4T1 and TS/A mammary carcinomas, and CT26 colon carcinoma) tumors. We report that although MDSCs express functional IFN‐γR and IL‐4Rα, and have the potential to signal through the STAT1 and STAT6 pathways, respectively, neither IFN‐γ nor IL‐4Rα impacts the phenotype, accumulation, or T‐cell suppressive potency of MDSCs, although IFN‐γ and IL‐4Rα modestly alter MDSC‐macrophage IL‐10 crosstalk. Therefore, neither IFN‐γ nor IL‐4Rα is a key regulator of MDSCs and targeting these molecules is unlikely to significantly alter MDSC accumulation or function.