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The gas synthesis of nanoparticles has gained major interest by different industries and research groups for the development of new materials and their subsequent implementation in numerous devices and applications. Actually, there are numerous research and application activities in flame-based nanoparticle production, mainly focusing on the process and its development, the in situ and ex situ analyses in experiments and simulations and new material and material combination developments. This review provides an overview on the flame synthesis of metal oxide nanoparticles and focuses in particular on the process design of flame spray pyrolysis (FSP). The first part of this review describes the historical background of flame-based particle production and further summarizes the emerging developments, achievements, and trends during the past 2 decades. The second part covers a general process overview of the flame aerosol-based manufacturing by explaining the key aspects of synthesis (chemical raw materials, metal precursors, solvents, and reactor configurations), in situ conditioning approaches, and powder and byproduct collection, along with additional post-processing steps (storage, handling, and modification). Applications of flame-made nanoparticles involve catalysts, gas sensors, energy storage materials, and nanotoxicity studies, among others, which will not be discussed in detail but are overviewed by listing the latest reviews of the respective field. The third part focuses on the growth mechanisms of solid particle products in liquid droplet/spray pyrolysis (liquid-to-particle and gas-to-particle conversion). The concept of characteristic process times is then exemplified for a lab-scaled FSP reactor, while afterward, particle dynamics and continuum models for reactor simulation are reviewed. The fourth part is a survey of more than 20 different diagnostic techniques that are commonly employed for characterization of reactive sprays and flame-made powders. We briefly explain the metrology basics of each method, indicate advantages and limitations, and present exemplary measurement results that have been acquired on flame reactor facilities for particle synthesis. Finally, we summarize the review and address some current challenges that might potentially shape the near future of nanoparticle synthesis in flame sprays.