In this work we investigate the advantages of multiscale methods in Petrov-Galerkin (PG) formulation in a general framework. The framework is based on a localized orthogonal decomposition of a high dimensional solution space into a low dimensional multiscale space with good approximation properties and a high dimensional remainder space, which only contains negligible fine scale information. The multiscale space can then be used to obtain accurate Galerkin approximations. As a model problem we consider the Poisson equation. We prove that a Petrov-Galerkin formulation does not suffer from a significant loss of accuracy, and still preserve the convergence order of the original multiscale method. We also prove inf-sup stability of a PG continuous and a discontinuous Galerkin finite element multiscale method. Furthermore, we demonstrate that the Petrov-Galerkin method can decrease the computational complexity significantly, allowing for more efficient solution algorithms. As another application of the framework, we show how the Petrov-Galerkin framework can be used to construct a locally mass conservative solver for two-phase flow simulation that employs the Buckley-Leverett equation. To achieve this, we couple a PG discontinuous Galerkin finite element method with an upwind scheme for a hyperbolic conservation law.