The extensive investigation of the human microbiome and the accumulating evidence regarding its critical relationship to human health and disease has advanced recognition of its potential as the next frontier of drug development. The rapid development of technologies, directed at understanding the compositional and functional dynamics of the human microbiome, and the ability to mine for novel therapeutic targets and biomarkers are leading innovative efforts to develop microbe-derived drugs that can prevent and treat autoimmune, metabolic, and infectious diseases. Increasingly, academics, biotechs, investors, and large pharmaceutical companies are partnering to collectively advance various therapeutic modalities ranging from live bacteria to small molecules. We review the leading platforms in current development focusing on live microbial consortia, engineered microbes, and microbial-derived metabolites. We will also touch on how the field is addressing and challenging the traditional definitions of pharmacokinetics and pharmacodynamics, dosing, toxicity, and safety to advance the development of these novel and cutting-edge therapeutics into the clinic.