The ability of the immune system to specifically recognize millions of different antigens and antigenic epitopes is based on the enormous diversity (at least 1012) of antigen-specific receptors, that is, surface membrane-bound immunoglobulin (smIg) molecules on B-lymphocytes and T-cell receptor (TCR) molecules on T-lymphocytes. The antigen-specific receptors differ from lymphocyte to lymphocyte, but each single lymphocyte or lymphocyte clone expresses approximately 105 receptors with identical antigen specificities. The extensive diversity of the antigen-specific receptors of lymphocytes is based on rearrangement processes in the genes encoding the Ig/TCRs (IG/TCR). Since the various types of lymphoid leukemia resemble normal lymphoid (precursor) cells, most lymphoid leukemias and lymphomas also contain rearranged IG/TCRs. Being derived from a single malignantly transformed lymphoid cell, all cells of a lymphoid malignancy have their IG/TCR genes rearranged in an identical way. This information can be readily employed for clonality assessment in lymphoproliferations. The IG/TCR rearrangement processes and the methods for detecting their clonal rearrangements in various types of (childhood) leukemia will be discussed. Finally, several applications of diagnostic clonality studies in childhood leukemia are presented.