Sex-based differences in insulin resistance are a key factor in the development and progression of metabolic diseases such as diabetes and obesity. Women are generally more insulin sensitive than men, but this advantage diminishes after menopause or when insulin resistance progresses to hyperglycemia and diabetes. This review discusses the pathophysiology of insulin resistance, the epidemiological evidence of sex-based differences, and the biological factors contributing to these differences. It focuses on differences in body fat distribution, muscle mass, inflammation, and sex hormones between males and females. The review also highlights the significant mechanistic differences in insulin sensitivity and glucose and lipid metabolism in key metabolic organs: liver, white adipose tissue, and skeletal muscle. It discusses the sex-based differences in response to interventions and identifies important open research questions. Insulin resistance is characterized by defects in the activation of intracellular signaling pathways after insulin binding to the insulin receptor. The main pathway mediating insulin effects is the PI3K-AKT pathway. Defects in this pathway contribute to insulin resistance. Inflammation in adipose tissue, driven by high free fatty acid uptake, creates a proinflammatory environment that promotes insulin resistance. Lipotoxicity, caused by lipid overload in adipocytes, leads to endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction, further exacerbating insulin resistance. In skeletal muscle, lipid overload is the predominant mechanism of insulin resistance. Inflammation and metabolic stress in adipose tissue and skeletal muscle are influenced by sex hormones, particularly estrogen and testosterone. Estrogen improves insulin sensitivity by regulating insulin secretion and modulating signaling in metabolic organs. Testosterone also plays a role in metabolic health, with lower levels associated with increased insulin resistance and diabetes risk. Sex hormones, body fat distribution, and inflammation are key factors in sex-based differences in insulin resistance. Women tend to have more subcutaneous fat and less visceral fat, which is associated with lower insulin resistance. Menopause leads to increased visceral fat and insulin resistance. Estrogen replacement therapy can improve insulin sensitivity and reduce diabetes risk in postmenopausal women. Testosterone levels are lower in obese men with diabetes, and low testosterone is associated with insulin resistance and cardiovascular disease. Body fat distribution and composition differ between men and women, with women having a higher capacity for non-oxidative clearance of free fatty acids. These differences are influenced by sex hormones and may contribute to the sex-based differences in insulin resistance and metabolic health. Inflammation in adipose tissue and skeletal muscle is also sex-dependent, with women showing less inflammation and better insulin sensitivity. The role of gut microbiota in sex-based differences in insulin resistance is also discussed, with differences in microbial composition and function between men and women. Overall, sex-based differences in insulin resistance are influenced by a complex interplay of hormonal, metabolic, and inflammatory factors.Sex-based differences in insulin resistance are a key factor in the development and progression of metabolic diseases such as diabetes and obesity. Women are generally more insulin sensitive than men, but this advantage diminishes after menopause or when insulin resistance progresses to hyperglycemia and diabetes. This review discusses the pathophysiology of insulin resistance, the epidemiological evidence of sex-based differences, and the biological factors contributing to these differences. It focuses on differences in body fat distribution, muscle mass, inflammation, and sex hormones between males and females. The review also highlights the significant mechanistic differences in insulin sensitivity and glucose and lipid metabolism in key metabolic organs: liver, white adipose tissue, and skeletal muscle. It discusses the sex-based differences in response to interventions and identifies important open research questions. Insulin resistance is characterized by defects in the activation of intracellular signaling pathways after insulin binding to the insulin receptor. The main pathway mediating insulin effects is the PI3K-AKT pathway. Defects in this pathway contribute to insulin resistance. Inflammation in adipose tissue, driven by high free fatty acid uptake, creates a proinflammatory environment that promotes insulin resistance. Lipotoxicity, caused by lipid overload in adipocytes, leads to endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction, further exacerbating insulin resistance. In skeletal muscle, lipid overload is the predominant mechanism of insulin resistance. Inflammation and metabolic stress in adipose tissue and skeletal muscle are influenced by sex hormones, particularly estrogen and testosterone. Estrogen improves insulin sensitivity by regulating insulin secretion and modulating signaling in metabolic organs. Testosterone also plays a role in metabolic health, with lower levels associated with increased insulin resistance and diabetes risk. Sex hormones, body fat distribution, and inflammation are key factors in sex-based differences in insulin resistance. Women tend to have more subcutaneous fat and less visceral fat, which is associated with lower insulin resistance. Menopause leads to increased visceral fat and insulin resistance. Estrogen replacement therapy can improve insulin sensitivity and reduce diabetes risk in postmenopausal women. Testosterone levels are lower in obese men with diabetes, and low testosterone is associated with insulin resistance and cardiovascular disease. Body fat distribution and composition differ between men and women, with women having a higher capacity for non-oxidative clearance of free fatty acids. These differences are influenced by sex hormones and may contribute to the sex-based differences in insulin resistance and metabolic health. Inflammation in adipose tissue and skeletal muscle is also sex-dependent, with women showing less inflammation and better insulin sensitivity. The role of gut microbiota in sex-based differences in insulin resistance is also discussed, with differences in microbial composition and function between men and women. Overall, sex-based differences in insulin resistance are influenced by a complex interplay of hormonal, metabolic, and inflammatory factors.