The 2022 outbreak of monkeypox (MPX) in non-endemic regions has raised global concern, highlighting the need for a deeper understanding of the virus and its interactions with the host. MPX is a DNA virus belonging to the *Orthopoxvirus* genus, causing a zoonotic infection. The virus has two main genetic clades: Clade I, prevalent in Central Africa, associated with more severe disease and higher mortality, and Clade II, endemic in West Africa, linked to milder symptoms and lower mortality. MPX primarily infects oral and respiratory mucosal tissues, leading to fever, headache, lymphadenopathy, muscle aches, and rashes. The virus spreads through respiratory droplets, sexual activities, and close contact with lesions. Host immune responses play a crucial role in defending against MPX, but the virus has evolved multiple strategies to evade these defenses. These include preventing the production of interferons (IFNs), blocking IFN-induced signaling pathways, inhibiting immune cell activation, regulating apoptosis, and modulating inflammasomes. The virus also employs unique mechanisms, such as targeting the cGAS-STING/MITIA pathway and inhibiting the N-terminal domain of the F3 protein, to evade immune responses. Vaccines and therapeutics developed for smallpox are effective against MPX, including JYNNEOS and ACAM2000 vaccines, and Tecovirimat and Brincidofovir for treatment. However, there is an urgent need for MPX-specific vaccines and drugs, especially for vulnerable populations like children, pregnant women, and immunocompromised individuals. Understanding the unique immune evasion mechanisms of MPX and the distinct mechanisms of host defense regulation by the two clades is essential for developing effective antiviral strategies and vaccines. Future research should focus on these areas to improve our understanding of MPX-host interactions and enhance the development of preventive and therapeutic measures.The 2022 outbreak of monkeypox (MPX) in non-endemic regions has raised global concern, highlighting the need for a deeper understanding of the virus and its interactions with the host. MPX is a DNA virus belonging to the *Orthopoxvirus* genus, causing a zoonotic infection. The virus has two main genetic clades: Clade I, prevalent in Central Africa, associated with more severe disease and higher mortality, and Clade II, endemic in West Africa, linked to milder symptoms and lower mortality. MPX primarily infects oral and respiratory mucosal tissues, leading to fever, headache, lymphadenopathy, muscle aches, and rashes. The virus spreads through respiratory droplets, sexual activities, and close contact with lesions. Host immune responses play a crucial role in defending against MPX, but the virus has evolved multiple strategies to evade these defenses. These include preventing the production of interferons (IFNs), blocking IFN-induced signaling pathways, inhibiting immune cell activation, regulating apoptosis, and modulating inflammasomes. The virus also employs unique mechanisms, such as targeting the cGAS-STING/MITIA pathway and inhibiting the N-terminal domain of the F3 protein, to evade immune responses. Vaccines and therapeutics developed for smallpox are effective against MPX, including JYNNEOS and ACAM2000 vaccines, and Tecovirimat and Brincidofovir for treatment. However, there is an urgent need for MPX-specific vaccines and drugs, especially for vulnerable populations like children, pregnant women, and immunocompromised individuals. Understanding the unique immune evasion mechanisms of MPX and the distinct mechanisms of host defense regulation by the two clades is essential for developing effective antiviral strategies and vaccines. Future research should focus on these areas to improve our understanding of MPX-host interactions and enhance the development of preventive and therapeutic measures.