Santa Cruz is located at the left bank of the Pasig River, on the northern portion of the City of Manila, near the mouth of the river, in between the districts of Tondo and Quiapo. The district belongs to the 3rd congressional district of Manila in the Philippines.During the American period, San Lazaro was transformed into a center for communicable diseases, caring for those afflicted with bubonic plague, cholera, smallpox, venereal diseases and diphtheria. The care for the lepers during the American period was transferred to a new location, farther north into what is now Caloocan City.
The whole district of Santa Cruz can be traversed through its main thoroughfare, Rizal Avenue (or formerly called Avenida Rizal). The area near Santa Cruz Parish all the way to Quiapo became known as "downtown", the center of commercial and trading activity.
Rows of bazaars and theaters, including those featuring vaudeville opened for business along Rizal Avenue. A row of art deco style buildings averaging three to four stories were built in the area and for a generation, a number of shoppers trooped to the area for bargain buys and to be entertained.