This review aimed to be comprehensive and to critically analyze the factors that may affect the macronutrient and energy content of breast milk. Systematic reviews were prioritized, even though other types of literature reviews on the subject, as well as studies not included in these reviews, were included. Reported factors that potentially affect the macronutrient and energy content of breast milk comprise: maternal factors, such as age, nutritional status, dietary intake, smoking habits, lactation stage, circadian rhythmicity, and the use of galactagogues; obstetrical factors, such as parity, preterm delivery, multiple pregnancies, labor and delivery, and pregnancy morbidities including intrauterine growth restriction, hypertensive disorders, and gestational diabetes mellitus; and newborn factors, including sexual dimorphism, and anthropometry at birth. Some factors underwent a less robust assessment, while others underwent a more in-depth analysis. For example, the milk from overweight and obese mothers has been reported to be richer in energy and fat. A progressive decrease in protein content and an increase in fat content was described over time during lactation. The milk from mothers with hypertensive disorders may have a higher protein content. Higher protein and energy content has been found in early milk from mothers who delivered prematurely.