Abstract: Trinucleotide and tetranucleotide repeat disorders are genetic inheritable diseases caused by mutations in DNA where the repeats in certain genes exceed the normal size. Once the repeats are transcribed, mRNA folds into a hairpin with repeating CXG (X = C, A, G, U) or CCUG motifs, which either attract cytoplasmic multiprotein complexes or translate into toxic polyQ proteins and cause the disease. These mRNA repeats have 1×1 or 2×2 internal loops, which make them ideal targets for pharmacologic development. Yet, the dynamic nature of RNA loops presents a significant challenge to obtaining reasonable predictions for targeting RNA repeats with small molecules. Two important results from our recent studies provide a point of entry into this challenging problem. First, we found that 1×1 AA internal loops in RNA CAG repeat expansions are dynamic and can form multiple different stable conformations; and second, we found that targeting 1×1 UU and 2×2 CU/UC internal loops with a small molecules produced complex structural changes in the RNA loop conformations with lowest free energy structures corresponding to one of the local minimum states predicted for 1×1 AA internal loops. These results suggest that RNA internal loops have multiple different free energy minimum states, which could be dominated with small molecules upon binding.