Computer simulations are carried out to characterize the variation of spin-crossover (SCO) behavior of the prototypical {Fe(pz)[Pt(CN)(4)]} metal-organic framework (MOF) upon adsorption of chemically and structurally different guest molecules. A detailed analysis of both strength and anisotropy of guest molecule framework interactions reveals direct correlations between the mobility of the guest molecules inside the MOF pores, the rotational mobility of the pyrazine rings of the framework, and the stabilization of the low-spin state of the material. On the basis of these correlations, precise molecular criteria are established for predicting the spin state of {Fe(pz)[Pt(CN)(4)]} upon guest adsorption. Finally, predictions of the SCO temperature upon adsorption of various toxic gases demonstrate that in silico modeling can provide fundamental insights and design principles for the development of spin-crossover MOFs for applications in gas detection and chemical sensing.