Spirulina is a microalga recognized for its nutritional benefits and its potential in sustainable food production. Existing large-scale cultivation produces spirulina of very different quality, taste, and odor. The reason lies in various approaches to the production, which range from the low-technology simple systems to high-end high-quality production for more demanding consumer market. In this chapter, we present challenges and possible solutions to ensure production of high-grade spirulina. We describe the design and crucial demands that have to be assured in the production system. The quality and productivity can be further increased by applying a bioprocess engineering approach based on modeling of the cultivation. Thermal modeling is also presented as an approach to optimize cultivation in the greenhouse systems. A spirulina production in Italy is showcased to pinpoint challenges of spirulina production in Europe. We conclude with an extensive study of regulatory framework for the spirulina production that must be taken into account for the successful algae production.