Abstract: This chapter presents a third-order predictive modelling methodology which aims at obtaining best-estimate results with reduced uncertainties (acronym: 3rd-BERRU-PM) for applications to large-scale models comprising many parameters. The building blocks of the 3rd-BERRU-PM methodology include quantification of third-order moments of the response distribution in the parameter space using third-order adjoint sensitivity analysis (which overcomes the curse of dimensionality), assimilation of experimental data, model calibration, and posterior prediction of best-estimate model responses and parameters with reduced best-estimate variances/covariances for the predicted responses and parameters. Applications of these concepts to an inverse radiation transmission problem, to an oscillatory dynamical model, and to a large-scale computational model involving 21,976 uncertain parameters, respectively, are also presented, thus illustrating the actual computation and impacts of the first-, second-, and third-order response sensitivities to parameters on the expectation, variance, and skewness of the respective model responses.