We designed an individual-based simulation model to explore the effects of landscape spatial structure and connectivity on the population size and persistence of two woodland small mammal species, eastern chipmunks (Tamias striatus) and white-footed mice (Peromyscus leucopus), occurring in an agricultural landscape and occupying different positions on a gradient of behavioural flexibility in response to landscape change. Chipmunks represent a less flexible response, retaining their preference for wooded habitat. White-footed mice represent a more flexible, opportunistic response, expanding their use of the landscape to include corn and small-grain fields. Model parameters were derived from out field studies. The simulations followed chipmunk populations over 25 yr in 36 landscape patterns, each with a unique combination of amount of wooded habitat (10%, 30%, or 50% of the total area), subdivision of wooded habitat (2, 4, or 8 patches), and quality of connectivity (high, intermediate, low, or none). Mouse populations were simulated in 8 of these landscapes (30%, wooded habitat, 4 patches at each level of connectivity, and 10% wooded habitat, 8 patches at each level of connectivity). Generalist mice outperformed specialist chipmunks in all subdivided landscapes in which they were compared. Since generalist mice were not restricted to woods and fencerows, all landscapes were highly connected for them and provided over 75% usable habitat. Survival rates for these mice were high in all landscape patterns. For opportunistic species able to use novel resources, landscape change may not be limiting. Connectivity was the best predictor of population persistence for specialist species that view the matrix as hostile. Chipmunk population survival was always greater in connected landscapes than in unconnected ones. Interactions of connectivity, composition and configuration were also important. Long survival times and low probabilities of extinction for chipmunk populations occurred in model landscapes with 30% or more woodland, and high and intermediate quality connectivity. Chipmunk populations in 8 patch landscapes with only 10% woodland and low connectivity had high extinction probabilities. Highly variable population size increased risk of extinction, especially when amount of wooded habitat was low. For behaviourally inflexible species, maintenance of habitat connectivity when habitat subdivision and accompanying habitat loss occur is vital to survival.