The cuprizone model is a widely used tool in pre-clinical research to study oligodendrocyte degeneration, demyelination, and remyelination in multiple sclerosis (MS). This article provides a comprehensive guide for conducting pre-clinical trials using the cuprizone model in mice, focusing on discovering new treatment approaches to prevent oligodendrocyte degeneration or enhance remyelination. The cuprizone model induces selective oligodendrocyte stress and subsequent demyelination, which can be followed by endogenous remyelination if animals are provided with a regular diet after the initial treatment. Key aspects of the model include the timing and duration of cuprizone exposure, the assessment of oligodendrocyte degeneration and demyelination, and the evaluation of remyelination. The article highlights the importance of using consistent experimental conditions, such as the specific brain regions and time points for analysis, to ensure reliable results. Additionally, it discusses the role of different cell death modalities, such as apoptosis and ferroptosis, in oligodendrocyte degeneration and the potential therapeutic targets for preventing or mitigating these processes. The cuprizone model is particularly useful for studying the mechanisms of demyelination and remyelination, and it offers a valuable platform for developing novel therapeutic strategies for MS and other myelin-related disorders.The cuprizone model is a widely used tool in pre-clinical research to study oligodendrocyte degeneration, demyelination, and remyelination in multiple sclerosis (MS). This article provides a comprehensive guide for conducting pre-clinical trials using the cuprizone model in mice, focusing on discovering new treatment approaches to prevent oligodendrocyte degeneration or enhance remyelination. The cuprizone model induces selective oligodendrocyte stress and subsequent demyelination, which can be followed by endogenous remyelination if animals are provided with a regular diet after the initial treatment. Key aspects of the model include the timing and duration of cuprizone exposure, the assessment of oligodendrocyte degeneration and demyelination, and the evaluation of remyelination. The article highlights the importance of using consistent experimental conditions, such as the specific brain regions and time points for analysis, to ensure reliable results. Additionally, it discusses the role of different cell death modalities, such as apoptosis and ferroptosis, in oligodendrocyte degeneration and the potential therapeutic targets for preventing or mitigating these processes. The cuprizone model is particularly useful for studying the mechanisms of demyelination and remyelination, and it offers a valuable platform for developing novel therapeutic strategies for MS and other myelin-related disorders.