Microglia, specialized immune cells unique to the central nervous system (CNS), exhibit highly plastic morphology that changes rapidly in response to injury or infection. Qualitative and quantitative assessments of microglial morphology are crucial for understanding neuroinflammation and microglial reactivity. While microglial morphology is a useful marker of inflammation and tissue damage, it is not synonymous with microglial function. The functions of distinct microglial morphologies are not fully understood, and microglial reactivity is influenced by multiple coordinated factors. This review discusses the importance of combining histological and genetic approaches to comprehensively examine microglial reactivity. Immunohistochemistry-based analyses, particularly those using markers like Iba1, CX3CR1, and CSF-1R, are essential for answering many research questions. Additionally, in vivo techniques such as multiphoton microscopy and neuroimaging methods like PET and MRI provide valuable insights into microglial morphology and function. The review highlights the need for standardized methods and caution in interpreting morphological data to ensure accurate biological conclusions.Microglia, specialized immune cells unique to the central nervous system (CNS), exhibit highly plastic morphology that changes rapidly in response to injury or infection. Qualitative and quantitative assessments of microglial morphology are crucial for understanding neuroinflammation and microglial reactivity. While microglial morphology is a useful marker of inflammation and tissue damage, it is not synonymous with microglial function. The functions of distinct microglial morphologies are not fully understood, and microglial reactivity is influenced by multiple coordinated factors. This review discusses the importance of combining histological and genetic approaches to comprehensively examine microglial reactivity. Immunohistochemistry-based analyses, particularly those using markers like Iba1, CX3CR1, and CSF-1R, are essential for answering many research questions. Additionally, in vivo techniques such as multiphoton microscopy and neuroimaging methods like PET and MRI provide valuable insights into microglial morphology and function. The review highlights the need for standardized methods and caution in interpreting morphological data to ensure accurate biological conclusions.