Purpose <p>This narrative review aims to explore the critical roles of growth factors and cytokines in tissue regeneration and repair, from fundamental mechanisms to clinical translation. The review focuses on their structure–function relationships, therapeutic applications, and innovative engineering strategies employed to overcome pharmacological challenges in their clinical translation.</p> Methods <p>This review encompasses current knowledge and findings from key studies in the field, emphasizing the interplay of growth factors, cytokines, and biomaterials. Advances in delivery systems and engineering approaches are discussed to highlight their impact on therapeutic outcomes in bone, cartilage, and neural regeneration.</p> Results <p>Growth factors such as BMPs, FGFs, and VEGFs, along with cytokines like IL-10 and SDF-1, coordinate tissue repair through key cellular processes, including proliferation, differentiation, angiogenesis, and immune modulation. Innovations in precisely engineered biomaterial-based delivery platforms, including stimuli-responsive hydrogels and targeted nanoparticles, enable tissue-specific spatiotemporal control and enhance bioavailability. Clinical successes in bone and cartilage regeneration and neural repair demonstrate the promise of these approaches, though challenges such as short half-life and immunogenicity remain significant barriers.</p> Conclusions <p>While growth factors and cytokines represent a cornerstone of regenerative medicine, their optimal clinical application requires integration of advanced engineering strategies with patient-specific approaches to address stability, delivery, and cost challenges. Emerging technologies such as CRISPR-edited variants and AI-designed biomimetic scaffolds hold the potential to unlock their full therapeutic potential of these biomolecules, enabling more effective and personalized treatments across musculoskeletal, neural, and cardiovascular applications.</p> Lay Summary <p>Growth factors and cytokines are essential molecules that regulate tissue repair by promoting cell growth, differentiation, and inflammation control. They are being developed into therapies for conditions like bone fractures, cartilage damage, and spinal cord injuries. However, challenges such as rapid degradation and immune responses limit their effectiveness. To address this, innovative delivery systems like hydrogels and nanoparticles are being used to protect and precisely release these molecules at the site of injury. Advances in biomaterials and engineering technologies, including gene editing, aim to enhance their stability and efficacy. These developments show promise in creating safer, more effective, and personalized regenerative treatments for a wide range of conditions.</p>