High-sensitivity differential scanning calorimetry (HSDSC) is widely used to examine the thermal behaviour of biomolecules and water-soluble polymers in aqueous solution. The principal purpose of this manuscript is to examine the thermodynamic basis for the signals obtained using HSDSC. It is shown that a combination of the van't Hoff isochore and Kirchhoff's equation are all that is necessary to simulate and curve fit the HSDSC output obtained for the thermally induced unfolding of the protein ubiquitin. The treatment is further developed to show how the temperature dependence of the heat capacity change of unfolding, multiple sequential transitions, and protein dissociation can be incorporated into the thermodynamic description of protein unfolding and how these factors in turn affect the HSDSC signal.