Serine “magic-number” clusters have attracted substantial experimental and theoretical interest since their discovery. These clusters have been implicated in one possible mechanism leading to the origin of homochirality, as octamers of serine exhibit remarkable stability and chiral selectivity. Here we develop a “structural landscape” of serine clusters using a variety of theoretical and experimental methods. We develop an initial set of candidate structures for many cluster sizes and all possible enantiomeric configurations via a simulated annealing molecular dynamics method. Further optimization and high-level single-point energy calculations are then performed with DFT for neutral and ionized structures. Stochastic dynamics of serine and other amino acids in explicit solvent are performed as a probe of solution phase dynamics. These results are aimed to resolve outstanding issues associated with the thermochemistry of serine clusters, the remarkable stability of the homochiral octamer, and the mechanism leading to their formation.