The Myc/Max/Mad proteins are basic region-helix-loop-helix-leucine zipper (b/HLH/LZ) transcription factors that regulate the transcription of numerous genes involved in cell growth and proliferation. The Max protein is the obligate heterodimeric partner of the Myc and Mad proteins. Heterodimerization and DNA binding to target gene promoters are mediated by the b/HLH/LZ domains. Max can also form a homodimeric b/HLH/LZ. The enhanced expression of Myc and binding to promoters of target genes contribute to almost every aspect of tumor biology. However, the detailed mechanism by which dimeric and heterodimeric b/HLH/LZs discriminate cognate DNA (E-Box: CACGTG) from non-specific sequences in the target gene promoters is still unknown. Here, we use the Max b/HLH/LZ homodimer as a model for this class of transcription factors in the characterization and understanding of the mechanism of discrimination between the E-Box and non-specific DNA sequences. We report the characterization of a cognate and a non-specific Max b/HLH/LZ/DNA complex by EMSA, CD and NMR. Our results support a detailed mechanism by which dimeric b/HLH/LZ transcription factors can discriminate E-Box sequences from non-specific DNA. The mechanism proceeds via the conformational selection of fitting b/HLH/LZ homodimers with the basic region only partially helical. Next, the basic region undergoes a DNA-assisted folding or induced-fit. It is this step that provides the discrimination by stabilizing and destabilizing the alpha-helical conformation of the basic region in the cognate and non-specific complexes, respectively. This leads to a low affinity complex with a higher probability of being dissociated and hence to discrimination. A description of the side-chains and nucleotides proposed to be involved in the discrimination process is provided.