We describe theoretical and experimental investigations of the nucleation of lattice mismatch-accommodating dislocations in the strained GexSi1−x /Si(100) system. Experimentally it is found that at lower mismatches nucleation appears to be associated with growth defects, while at higher x, surface loop nucleation is favored. Theoretical predictions of the magnitude of activation barriers for homogeneous nucleation of dislocation half-loops at the growth surface decline dramatically with increasing lattice mismatch (higher x), with nucleation of mixed climb and glide (90°) loops favored to pure glide (60°) loops. These activation barriers for surface half-loops are shown to be lower than previously calculated due to consideration of the random alloy nature of the GexSi1−x epilayer.