Modern relocation constrains the hypocenter of the 18 April 1906 California earthquake within an ∼8×24 km, southwest–northeast trending zone to the north of San Francisco that intersects the offshore San Andreas fault system west of San Francisco. Here we further constrain the location of the 1906 focus and examine the tectonics of the focal region using recent microseismicity relocated in a 3D model along with other seismological, geological, and marine evidence. In agreement with previous work, we associate the 1906 focus with an extensional, right stepover in the San Andreas fault system—a zone of sea floor subsidence and complex, normal, and strike-slip faulting. We define a likely focal volume between Lake Merced and offshore of the Golden Gate centered near 37.77° N, 122.55° W, and 10-km depth. We hypothesize possible 1906 rupture in this region by normal deformation around a 10-km-long, steeply west-dipping structure trending about 20° clockwise to the San Andreas fault zone, and bilateral, strike-slip fault rupture along the San Andreas fault system away from this structure: rupture to the northwest on a vertical, currently aseismic faulting structure under the Golden Gate fault and rupture to the southeast under the San Francisco peninsula either along a steeply southwest-dipping structure showing present-day extensional tectonism, or along a near-vertical, currently aseismic fault zone. All three of these structures extend from the near surface to about 10-km depth. We also identify a deeper, 15–20-km-long linear trend of clustered seismicity at 10–13-km depth, rotated about 6° clockwise relative to the strike of the San Andreas fault, which connects the north end of the focal volume with the south end of the seismicity defining the southwest-dipping structure under the San Francisco peninsula. We propose that this trend shows faulting at the base of a brittle, upper crust in response to underlying shear in a ductile, lower crust. These interpretations on the focal region of the 1906 earthquake have implications for seismotectonic understanding, earthquake monitoring, and seismic hazard assessment in the San Francisco Bay Area.