Mass spectrometry imaging (MSI) has become a powerful tool in diverse fields, such as chemistry, physics, materials, and life science. Although such research is getting more prevalent, it is limited by high-resolution (HR) instrumental development. Recently, unceasing efforts have been made toward taking spatial resolution from the microscale to nanoscale, especially for near-field based techniques. These emerging and unique features behind high-resolution mass spectrometry imaging (HR-MSI) provide new possibilities in various aspects of biological researches. Since many technological advances provided a forefront for HR-MSI, compelling challenges including sensitivity, specificity, multimodal imaging, data acquisition, and processing follow undoubtedly. Gratifyingly, with attempts and experiences in the infancy, the emerging techniques move toward much more mature to deal with underlying conundrums in the future. Not only confined to commercial instruments, this perspective highlights recent innovations covering all emerging HR-MSI (with spatial resolution below 5 μm) techniques. Besides, vital limitations and handicaps at this stage are presented while corresponding schemes are proposed. This perspective also gives the authors' personal outlooks of developments and applications for HR-MSI in coming years.