Lemnaceae, i.e., duckweed species, have gained considerable attention as a sustainable source of high-quality nutrition, biofuel, and pharmaceuticals, as well as effective organisms for phytoremediation of wastewaters. A protein content of up to 45% makes duckweed biomass nutritionally interesting as an ingredient for animal feeds or human food. Outdoor duckweed cultivation has become common in recent decades but can be difficult to optimise and to control operationally. Yet, duckweeds also represent a suitable crop for indoor farming, with most species due to their flat structure particularly suited for cultivation in multi-level (stacked) systems that use indoor floor space efficiently. Here we propose construction of stacked systems with up to 15 m2 of duckweed per m2 of floorspace. Such stacked systems are facilitated by limiting the water depth to about 5 cm. Indoor cultivation can maximise yields, and doubling times as short as 1.24 days have been reported under indoor conditions. Indoor cultivation also extends the scope for crop manipulation and enables cultivation under pest-free and even sterile conditions. Yet, the technical and operational parameters required for effective large-scale indoor cultivation of Lemnaceae have received scant attention in the literature. Here, it is concluded that technological advances in urban and/or vertical farming can be exploited to enable design and operation of novel duckweed cultivation systems. Recirculating, flow through technology can optimise nutrient supply and growth, while sensor support systems with artificial intelligence can facilitate autonomous cropping and even harvesting. Furthermore, advanced understanding of duckweed-biology can, amongst others, inform selection of (wastewater-based) media, flow-rates and media retention time, duckweed species and strains, and enhance performance through manipulation of the duckweed microbiome. Despite challenges and knowledge gaps, there are now realistic opportunities to develop and operate high capacity, autonomous, controlled cultivation of duckweed under indoor conditions, for a broad range of purposes.