Manipulations of nanocrystal (NC) surfaces have propelled the applications of colloidal NCs across various fields such as bioimaging, catalysis, electronics, and sensing applications. In this Feature Article, we discuss the surface chemistry of colloidal NCs, with an emphasis on semiconductor quantum dots, and the binding motifs for various ligands that coordinate NC surfaces. We present isothermal titration calorimetry (ITC) as a viable technique for studying the thermodynamics of the ligand association and exchange at NC surfaces by discussing its principles of operation and highlighting results obtained to date. We give an in-depth description of various thermodynamic models that can be used to interpret NC-ligand interactions as measured not only by ITC, but also by NMR, fluorescence quenching, and fluorescence anisotropy techniques. Understanding the complexity of NC surface-ligand interactions can provide a wide range of avenues to tune their properties for desired applications.