Affinity (the fastness) and specificity (the correctness) are the two important factors that decide the efficiency of a nucleic acid probe to target its specific site on a DNA lattice. DNA-probe interactions differ from protein-ligand interactions in a way that here the specificity and the affinity of the interactions correlate negatively with each other. We present a simple phenomenological theory to explain the negative correlation between the specificity and the affinity of the probe towards its target site on the template DNA under solution conditions. We show that a simple random jump model can explain this fact and we also predict that the negative correlation between the affinity and specificity diminishes as the temperature increases or the viscosity of the medium decreases. Moreover, the length of target DNA and the distance between the initial position of the probe on the template DNA lattice and the target site increases the magnitude of affinity-specificity negative correlation. These results are consistent with experimental observations. Finally we propose practical strategies to coherently improve the specificity and the affinity with respect to important molecular biological techniques such as PCR and Southern blotting. © 2005 Elsevier B.V. All rights reserved.