The diverse ecosystems, habitats, plants, and animals in the San Diego County region will be impacted by climatic shifts in multifold ways due to current and future variability, along with other factors including habitat loss and fragmentation, land use shifts, and changing fire regimes. While home to a major metropolitan area, San Diego County still hosts expanses of native and preserved habitats where management and conservation action could be greatly enhanced through science-based assessments and planning for climate change and increased climate variability. Projections of climate change in the region include warming by 4-9˚ F on average, and a 15-25% decrease in fall and spring precipitation with an increase in variability resulting in more frequent and intense droughts punctuated by increasingly rare yet extreme precipitation and flooding events. In addition, an increase in fire events and potential lessening of coastal marine influence may also affect San Diego’s ecosystems. Climate warming superimposed upon the pronounced spatially-varying temperature in the San Diego region will likely be associated with range shifts for many species resulting in novel community assemblages and biotic interactions and could create phenological mismatches. More frequent and intense heat waves may disproportionately affect younger age classes and reduce reproductive and survival rates of species sensitive to temperature extremes. With increasingly variable precipitation, drought may occur more frequently due to increased occurrence of dry days and could intensify because of warmer temperatures. Since drought disproportionately affects some species, these projected changes may cause structural changes to ecosystems. Santa Ana winds, occurring during increasingly dry fall months, would create ideal fire conditions. Coastal low clouds and fog along San Diego’s coast buffer this zone from the effects of warming and drying through shading and cooling. Although these marine stratus clouds will remain a presence, future changes in this phenomenon are uncertain. The spatial and temporal scales at which climate variations and change operate must be considered to build resilience into natural systems. Effective conservation actions will need to build on ongoing efforts focused on landscape-scale planning rather than more traditional single-species approaches. To carry this out will require cross-jurisdictional, multidisciplinary collaboration by scientists, policy-makers, planners, land managers, and the broader conservation community, which has a decades-long history of accomplishment in San Diego County.