Describing conformational changes in biomolecules using molecular dynamics simulations requires defining an appropriate low-dimensional mathematical description of the system, referred to as a set of collective variables (CVs). No single CV design strategy is universally optimal; the choice should be guided by the biological question, the property of interest, the evaluation criterion, and the chosen sampling method. Here, we discuss the physical principles that should inform CV design and categorize existing approaches. We also evaluate the relationship between different types of CVs, the amount of data required to train them, and suitable enhanced sampling approaches. Finally, we outline practical guidelines for selecting CVs, helping practitioners match methodological choices to the underlying dynamical process and to the goals of their simulations.