Misfolded protein neurodegeneration includes several pathologies characterized by the accumulation of a group of proteins that can modify their folding due to intrinsic or extrinsic factors, leading to the generation of aberrant forms characterized by their high insolubility, cytotoxicity, and the ability to propagate among various cell types and regions in affected brains. Due to this capacity and based on the properties of bona fide prions, a large number of “prion-like” or “prionoid” proteins with this ability have been described in recent years. Their study presents challenges, including the development of a detailed understanding of the processes involved in the formation of these insoluble aggregates and in establishing the cellular and molecular bases underlying the process of intercellular propagation. To address these processes, various laboratories have developed techniques to detect their presence in brain or peripheral samples. The detection of these molecules is, as of today, very effective and selective. However, the processes of transmission and propagation are not fully characterized. Indeed, various classical detection techniques have been developed, generally based on controlled polymerization processes and effective detection methods. Nevertheless, these conventional techniques have now incorporated various methodologies employed in other disciplines, such as nanotechnology, which have increased our understanding of these processes and are useful in the development of future therapies and drug discovery. In this chapter, we summarize the current state of the art of these conventional methods, their limitations, and the use of new platforms to deepen our understanding of these processes.