Human population is increasing from 7.6 billion today to an estimated 9.5–10 billion by 2050.1 How can billions more people, with increasing demands for protein and other food sources, be adequately fed without destroying the environment? Utilizing more land for agricultural purposes is not a solution, given that much of the arable land on the planet is already being used for food, fiber, chemical, or fuel production.2 One answer to this complex challenge will lie in the ability to produce more food within the current footprint in sustainable and affordable ways. By one definition, “an agricultural biologicals system is an ecologically, socially, and economically sustainable agricultural production system that promotes safe products by minimizing environmental adverse consequences and reducing the use of non-renewable natural resources.”3 In this article, we discuss opportunities that capitalize on twenty-first century technological innovation and the central role played by the microbial life intimately associated with plants: the plant and soil microbiomes. We examine the potential of Ag biologicals within the agricultural ecosystem. We elucidate their functionality as a means of increasing plant health and crop yields while maintaining environmental sustainability. Finally we illustrate the role that NewLeaf Symbiotics (St. Louis, MO) plays in the introduction of a range of Ag biologicals based on methylobacteria, or M-trophs—bio-complementary products that infuse plants with microbes that are tailored to fit specific crop genetics and environmental conditions.4 Most major agricultural input suppliers and seed companies recognize that biologicals represent a largely untapped opportunity to meet demand for novel and sustainable complements to the existing roster of agricultural chemicals, fertilizers, and genetically modified (GM) traits. Recent government, industrial, and private investments support the belief that significant improvements in crop productivity and environmental sustainability are achievable using complementary biological inputs. Between 2012 and 2015, over $2 billion was invested by Ag multinationals in agreements, mergers, and the acquisition of small biologicals companies.5 These investments are driving the development of the next generation of Ag biologicals. The broad recognition of the agricultural significance of the plant and soil microbiome is supported in large part by the reduced cost, increased speed, and improved accuracy of genomic sequencing. Simultaneous increases in computing power and analytics are driving the rapid evolution of new molecular biology tools directed at solving previously intractable problems. The recognition of the phyto-microbiome as a second genome, with the potential to supplement and interact with the plant genome, offers significant opportunity to improve crop health and yield.6 The persistent evolution of pest resistance to chemical pesticides and traits, combined with consumer demand for sustainable farming and food traceability, have created a strong and growing interest in new Ag biologicals.7 In the US there are 350-plus registered biocontrol agents based on 50-plus species. The market is growing at an average compounded annual growth rate (CAGR) greater than 14%. Every major international and domestic supplier of agronomic inputs is investing in this area. Since most Ag biological products are based on naturally occurring microbes, consumer health and safety concerns about these products are reasonably mitigated. Growers are aware and ready to try new biologicals, in part because biological products like rhizobia and Bacillus thuringiensis (Bt) have been used and accepted for decades. There are, however, significant obstacles to the introduction of novel and efficacious Ag biologicals. Microbes are part of extremely complex soil and plant systems; discovery and delivery of effective products are no simple tasks. Historically, some Ag biological market offerings failed to deliver consistent efficacy equal to conventional inputs, causing the industry to regard Ag biologicals with some caution. Improved strains, advanced formulations, and recognition of the unique value Ag biologicals can provide has led to an increase in their global market share over the past decade from less than 1% to more than 5%. Two of the major strategic challenges to increased use of Ag biologicals are: ▪ Optimization of discovery, screening, and derivation of candidate microbes, and ▪ Alignment of product development with technical and economic drivers of contemporary production farming.