Background: Limb lengthening surgery has evolved significantly, from external fixation methods to sophisticated motorized intramedullary nails (MILNs). This review critically examines the innovations in limb lengthening, particularly distraction osteogenesis and device technologies, and identifies persistent challenges such as pin-site infections, delayed bone consolidation, and ethical dilemmas associated with cosmetic limb lengthening. Additionally, we explore the potential of biomolecular therapies designed to activate stem cells for enhanced bone regeneration, with self-regulation to prevent uncontrolled cell proliferation and cancer. Methods: A systematic review was performed on 32 human studies (6 randomized controlled trials, 12 cohort studies, and 14 reviews) published between 2010 and 2025. Databases including PubMed, Scopus, Web of Science, and Cochrane CENTRAL were searched for studies examining lower-limb lengthening techniques, complication rates, biological adjuncts (bone morphogenetic protein-7, mesenchymal stem cells), and patient-reported outcomes. Study quality was assessed using RoB 2 for randomized trials and ROBINS-I for non-randomized studies. Data were extracted on device types, complications, biological treatments, and patient outcomes. Results: 1. PRECICE Max Nail: The FDA-approved PRECICE Max system, first implanted in February 2024, facilitates full weight-bearing from the start of distraction, reducing external frame use by 45% and alleviating discomfort by 30% compared to traditional methods. 2. Pin-Site Infections: A comparison between Ilizarov ring fixators and lengthening-over-nail devices revealed a 47.8% pin-site infection rate with the former, compared to 15.7% with the latter (odds ratio 0.32, 95% confidence interval 0.18–0.56). 3. Delayed Consolidation: Delayed bone consolidation was observed in 6–8% of cases using intramedullary nails, requiring extended treatment or reoperation. 4. Biological Adjuncts: Bone morphogenetic protein-7 reduced the healing index by 0.45 months per centimeter (95% confidence interval 0.28–0.62), and mesenchymal stem cell–seeded scaffolds increased regenerate bone density by 25% at 12 weeks. 5. Stem Cell Activation via Biomolecular Therapies: Emerging biomolecular therapies are designed to activate stem cells temporarily to accelerate bone formation, then undergo self-regulation or degradation to prevent prolonged activation and minimize tumor risk. Conclusions: The PRECICE Max system and advancements in biological adjuncts such as BMP-7 and MSC-seeded scaffolds represent major improvements in limb lengthening surgery. However, challenges related to delayed consolidation and infections remain. Biomolecular therapies offering controlled stem cell activation hold promise to enhance bone regeneration while minimizing cancer risks. These technologies, alongside artificial intelligence–driven personalized surgical planning, could significantly improve outcomes in limb lengthening surgery and regenerative medicine.