There is a growing recognition of the critical role microbes play in human health, with increasing evidence that engineered live biotherapeutics can target disease mechanisms directly. This chapter reviews recent advances in the development of recombinant live biotherapeutics (rLBPs), which include genetically and metabolically engineered microbial species designed to restore microbial balance, modulate immunity, and treat specific diseases through local action or gut-body axis interactions. Leveraging synthetic biology, genetic engineering, multi-omics, and artificial intelligence/machine learning (AI/ML) approaches, rLBPs are being designed for greater efficacy, regulatory acceptance, and clinical translation. While early studies show promising therapeutic potential, significant challenges remain in scalability, safety, and clinical application. This chapter highlights both the opportunities and hurdles in advancing rLBPs, emphasizing the need for continued innovation, rigorous clinical evaluation, and translational strategies to establish their role as next-generation therapeutics in human health.