The construction of models of system behavior is of great importance throughout science and engineering. In bioengineering and bionanotechnology, these often take the form of dynamic models that specify the evolution of different species over time. To ensure that scientific observations and conclusions are consistent and that systems can be reliably engineered on the basis of model predictions, it is important that models of biomolecular systems can be constructed in a reliable, principled, and efficient manner. This review focuses on efforts to address this need by using domain-specific programming languages as the basis for custom design tools for researchers working on computational nucleic acid devices, where a domain-specific language is simply a programming language tailored to a particular application domain. The underlying thesis of our review is that there is a continuum of practical implementation strategies for computational nucleic acid systems, which can all benefit from appropriate domain-specific languages and software design tools. We emphasize the need for specialized yet flexible tools that can be realized using domain-specific languages that compile to more general-purpose representations.