During adaptive immunity, B cells differentiate either into memory B cells or plasma cells and produce antibodies against foreign antigens to fight infection. Additionally, they behave as antigen-presenting cells and participate in T cell activation during cellular immune responses. However, their functional dysregulation can result in various autoimmune diseases and cancers. With significant breakthroughs in single cell technologies, assessing individual B cell genomics, transcriptomics, and proteomics can give deeper insights into mammalian B cell development, differentiation, antibody repertoire, and responses under conditions of homeostasis, infection, and aberrations during disease. In this review, we discuss the adoption of single cell approaches to identify different B cell gene signatures and biomarkers in normal and diseased tissues, and subsequent benefits for future therapeutic discoveries.