To start, sealing all of the large holes in the house will have the biggest effect. Plumbing, duct work, chimney chases, electrical work, and other service penetrations not intended for airflow or venting should be sealed where possible, no matter where they are in the house. It may seem obvious, but service penetrations are usually the leakiest areas of a house.
Once the large holes are sealed, the focus can be shifted to smaller, less obvious holes. At the basement or crawlspace, the rim joists should be sealed where the exterior wall meets the rim joist, and where the rim joist meets the foundation, as these areas can allow significant amounts of air into the home. Since cold air is drawn through these areas, air sealing can improve the thermal comfort of the home, and decrease heating costs.