<p>The paradigm of probiotic supplementation is shifting from a generic, one-size-fits-all model toward a precision-based approach tailored to the individual's unique microbiome. This review synthesizes current evidence on the development of personalized probiotic therapies, underpinned by advances in genomics and multi-omics technologies. We explore key probiotic genera—such as <i>Lactobacillus</i>, <i>Bifidobacterium</i>, and next-generation microbes—detailing their strain-specific mechanisms of action and functional roles in modulating host physiology. Our analysis of clinical applications reveals that personalized probiotic strategies can effectively reshape microbial community structure, enhance immune modulation, and ameliorate various conditions, including metabolic syndromes, gastrointestinal disorders, and neuroimmune diseases. Furthermore, we identify that the most successful interventions are those informed by pre-treatment microbial profiling, which predicts therapeutic efficacy. Despite this promise, significant challenges remain, including the lack of standardized frameworks for strain selection, limited large-scale clinical validation, and unresolved regulatory and ethical hurdles pertaining to data privacy and microbiome manipulation. This review concludes that while personalized probiotics hold immense potential to revolutionize therapeutic interventions by delivering targeted, safe, and effective microbial therapeutics, future research must prioritize the development of clinical guidelines and address these translational gaps to fully realize this potential.</p>