The intervertebral disc (IVD) is a fibrocartilaginous and composite tissue structure located between adjacent vertebrae with remarkable resiliency to cyclic loading. The IVD is comprised of a gelatinous hydrated core called the nucleus pulposus (NP) and is tightly held by rings of concentric collagen fibers called the annulus fibrosus (AF). Its unique composition and structure enable spinal stability, flexibility, and shock absorption from everyday movement. Over time, the progressive breakdown of the IVD due to age, injury, or illness results in the onset of degenerative disc disease (DDD). Eventually, this leads to weakening of the AF and depletion of disc extracellular matrix (ECM) components, resulting in poor load bearing capacity, reduced flexibility, recurrent pain, and profound disability. In fact, DDD and subsequent lower back pain is the leading cause of disability globally. Although biochemical changes are well documented in the degenerative IVD, current treatments are palliative and prioritize pain management as a means to delay surgical intervention. Moreover, surgical treatments fail to restore both native IVD composition and structure. With this in mind, the overarching goal of this dissertation is to develop bioactive and cell-based therapeutics for clinically relevant presentations of DDD. Chapter 1 reviews the challenges and innovations in developing bioactive therapies for early-stage degeneration, herniation, and end-stage degeneration. Chapter 2 investigates the safety and efficacy of intradiscal bone marrow aspirate concentrate (BMAC) injections following lumbar microdiscectomy in a phase 1 pilot study. Chapter 3 leverages a large animal model to investigate the capacity of a flexible support material to maintain disc height and support the formation of hydrated tissue engineered intervertebral discs (TE-IVDs) for total disc replacement. Chapter 4 employs CRISPR gene editing technology to regulate stem cell fate and enhance tissue deposition in composite TE-IVDs. Altogether, these findings represent a true bench-to-bedside approach, taking bioactive therapies from in vitro and in vivo studies to the assessment of their safety and efficacy in human patients.