The use of major histocompatibility complex (MHC) tetramers in the detection and analysis of antigen‐specific T cells has become more widespread since its introduction 11 years ago. Early challenges in the application of tetramer staining to CD4⁺ T cells centred around difficulties in the expression of various class II MHC allelic variants and the detection of low‐frequency T cells in mixed populations. As many of the technical obstacles to class II MHC tetramer staining have been overcome, the focus has returned to uncertainties concerning how oligomer valency and T‐cell receptor/MHC affinity affect tetramer binding. Such issues have become more important with an increase in the number of studies relying on direct ex vivo analysis of antigen‐specific CD4⁺ T cells. In this review we discuss which problems in class II MHC tetramer staining have been solved to date, and which matters remain to be considered.