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Over the past two decades revolutionary progress in plant biology became possible by focusing resources on a single plant reference system, Arabidopsis thaliana. After the completion of the Arabidopsis genome sequence in the year 2000, a coordinated multinational effort was launched to “determine the function of every gene in Arabidopsis” by the year 2010. While this ambitious goal has not yet been fully achieved, the Arabidopsis genome is now one of the best annotated and serves as the gold standard for plant and other genomes. A large and international community has established genetic toolkits and genomic resources, such as sequence-indexed mutant collections and comprehensive and easily accessible ‘omics-scale datasets, ranging from transcriptome over proteome to the metabolome. The Arabidopsis 2010 program evolved from the studying the functions of single genes and gene families to comprehensive systems-wide analyses of functional networks, thereby paving the way from descriptive to predictive plant science. Progress does not stop here – in the near future, the genomes of one thousand Arabidopsis strains and accessions will become available, which will make it possible to exploit existing natural variation for addressing fundamental questions in ecology and evolutionary biology in an unprecedented manner. Further, due to ease of transformation and existing genetic and genomic resources, Arabidopsis will likely serve as a chassis for synthetic plant biology, an emerging field and challenge for the next decade of plant research. This Research Topic of Frontiers in Plant Physiology will provide examples on how focusing on a single plant model system has impacted and revolutionized many fields of plant research and it will provide an outlook on the upcoming challenges and fields of research for the next decade of Arabidopsis research.