Patients with multiple myeloma have a clonal proliferation of malignant plasma cells, each with an identical rearrangement of immunogloblin heavy and light chain genes. When these unique sequences are determined, a valuable molecular tool is available that can been used to detect the presence of the malignant population. Previous methods have employed oligonucleotides derived from these sequences and allele-specific polymeraes chain reaction to detect clonality. The method described in this chapter uses mRNAin situhybridization (ISH) to demonstrate the presence of individual malignant cells. Single-cell analysis using mRNA ISH provides opportunities that when combined with immunophenotyping offer a valuable new investigative tool.