In recent years, owing to the advances in instrumentation, cryo-EM has emerged as the go-to tool for obtaining high-resolution structures of biomolecular systems. However, building three-dimensional atomic structures of biomolecules from these high-resolution maps remains a concern for the traditional map-guided structure-determination schemes. Recently, we developed a computational tool, Resolution Exchange Molecular Dynamics Flexible Fitting (ReMDFF) to address this problem by re-refining a search model against a series of maps of progressively higher resolutions, which ends with the original experimental resolution (Wang et al., J Struct Biol 204(2):319–328, 2018). In this chapter, we present a step-by-step outline for preparing, executing, and analyzing ReMDFF refinements of simple proteins and multimeric complexes. The structure determination of carbon monoxide dehydrogenase and Mg2+-channel CorA are employed as case studies. All scripts are provided via GitHub (Vant, Resolution exchange molecular dynamics flexible fitting (ReMDFF) all you want to know about flexible fitting, 2019, https://github.com/jvant/ReMDFF_Singharoy_Group.git).