Weight loss has profound effects on body composition and metabolism in people with obesity. Fat mass, fat-free mass, and resting energy expenditure decrease linearly with weight loss. Visceral adipose tissue and liver fat content decrease with small reductions in weight (2-5%) and decrease further with more weight loss. Hepatic inflammation, ballooning, and fibrosis require greater weight loss to improve (≥7-10%). Cardiometabolic risk factors (fasting glucose and insulin concentrations, glycated hemoglobin, lipid profile and blood pressure) improve with small reductions in weight (2-5%) and gradually thereafter with more weight loss. Skeletal muscle insulin sensitivity increases dose-dependently from 5% to 16% weight loss, whereas adipose tissue and hepatic insulin sensitivity and hepatic triglyceride secretion improve maximally with modest reductions in weight (5-10%) and do not improve further with more weight loss. Pancreatic insulin secretion does not respond to weight loss typically achieved by calorie restriction (≤15%) but may decrease after massive weight loss (≥17%). Weight loss dose-dependently reduces risk for diabetes, reduces the need for antidiabetic medications, and increases chances for diabetes remission. Apparently, weight loss even in amounts below what is considered clinically significant (5%) is beneficial for individuals with obesity, although more weight loss is almost always better.