In the biomedical field, the differentiation between sex and gender is crucial for enhancing the understanding of human health and personalizing medical treatments, particularly within the domain of orthopedics. This distinction, often overlooked or misunderstood, is vital for dissecting and treating musculoskeletal conditions effectively. This review delves into the sex- and gender-specific physiology of bones, cartilage, ligaments, and tendons, highlighting how hormonal differences impact the musculoskeletal system’s structure and function, and exploring the physiopathology of orthopedic conditions from an epidemiological, molecular, and clinical perspective, shedding light on the discrepancies in disease manifestation across sexes. Examples such as the higher rates of deformities (adolescent idiopathic and adult degenerative scoliosis and hallux valgus) in females and osteoporosis in postmenopausal women illustrate the critical role of sex and gender in orthopedic health. Additionally, the review addresses the morbidity–mortality paradox, where women, despite appearing less healthy on frailty indexes, show lower mortality rates, highlighting the complex interplay between biological and social determinants of health. Injuries and chronic orthopedic conditions such osteoarthritis exhibit gender- and sex-specific prevalence and progression patterns, necessitating a nuanced approach to treatment that considers these differences to optimize outcomes. Moreover, the review underscores the importance of recognizing the unique needs of sexual minority and gender-diverse individuals in orthopedic care, emphasizing the impact of gender-affirming hormone therapy on aspects like bone health and perioperative risks. To foster advancements in sex- and gender-specific orthopedics, we advocate for the strategic disaggregation of data by sex and gender and the inclusion of “Sexual Orientation and Gender Identity” (SOGI) data in research and clinical practice. Such measures can enrich clinical insights, ensure tailored patient care, and promote inclusivity within orthopedic treatments, ultimately enhancing the precision and effectiveness of care for diverse patient populations. Integrating sex and gender considerations into orthopedic research and practice is paramount for addressing the complex and varied needs of patients. By embracing this comprehensive approach, orthopedic medicine can move towards more personalized, effective, and inclusive treatment strategies, thereby improving patient outcomes and advancing the field.