This chapter discusses the thermodynamics and mutations in RNA-Protein interactions. The association between an RNA and a protein can be described by defining the local interactions between nucleotides and amino acids and by determining the energetics of the association. The local interactions show how the specificity of the association is conferred; the energetics will provide the assembly parameters that encompass both the individual interactions and their interdependence. To predict the properties of an RNA-protein interaction, it is necessary to know how the specificity and affinity of the interaction are controlled. The details of the association include how the RNA phosphate backbone is used in electrostatic interactions, where hydrogen bonds are formed between RNA and protein, if the two molecules associate to form a hydrophobic core of aromatic amino acids and nucleotides, where water molecules and counterions are used in the interaction, and if, in order to form these interactions, there is any conformational rearrangement of RNA or protein. While the thermodynamic parameters of the interaction certainly not provide all these details, they can suggest which features are likely to be important for the interaction, and provide a framework in which to construct an accurate model of the complex. One simple approach to uncover the interactions and energetics of RNA-protein complexes is to make a mutation in the RNA sequence and then measure the affinity of the protein for this RNA variant.