Santee's history begins with the establishment of the Old Mission Dam in 1779 under the direction of Fr. Junipero Serra.  The dam provided water to the Mission San Diego de Alcala, and the site is preserved in the historic Old Mission site near the western entrance to the town.

Eventually the land was parceled up into land grants and given to the Spanish soldiers.  It was sold to the first American settlers in 1877 when George Cowles bought 4,000 acres to develop his vineyards. The area was originally call Cowleston and became known as Santee after Cowles widow married Milton Santee.  Cowles Mountain is named for Cowles and preserves the memory of his early development of the area. The town was linked to San Diego by the Cuyamaca Railroad.

Santee's business climate is forging ahead thanks to its location and its convenient proximity to all areas of the county. Santee Town Center consists of 706 acres master planned for mixed use, and it is thriving, with over 1.1 million square feet of commercial development over the past decade. It also helps that Santee has the seventh highest median household income in the region and one of the lowest crime rates.
 
The centerpiece of the city's current prosperity is Santee Trolley Square, a transit-oriented shopping center built around the terminus of the trolley line that runs from Old Town to Santee, traversing through the Mission Valley corridor. Trolley Square features major retailers like Target; TJ Maxx; Bed, Bath & Beyond; Old Navy; Barnes & Noble; Pier 1 Imports and Staples. Shoppers can dine at an array of restaurants, including Mimi's Cafe, Olive Garden, Chili's, Original Roadhouse Grill, and Oggi's Pizza & Brewery. Other amenities include a 250-seat amphitheater and a food court.
 
Adjacent to Trolley Square, the city is on the verge of one its most significant developments. RiverView at Santee is a 104-acre mixed-use corporate campus, which has been master planned for 1.9 million square feet of technology, R&D and professional office uses along the San Diego River.

The first phase of this project was Hartford Financial Services, which moved its regional offices and 500 employees from Mission Valley to this new corporate campus. Construction is under way on the second phase of the RiverView Professional Center, comprising of 62,500 square feet of office buildings. Future plans also provide for 240 condominiums and a multiplex theater directly across from Trolley Square.
 
 
Retail is also the focus of new developments along Mission Gorge Road. Kohl's Department Store and Lowes Home Improvement anchor a 250,000-square-foot center that opened in late 2004, and an older shopping center is currently being redeveloped with a Henry's Market and other retailers across the street.
 
The Santee Plaza/Promenade is anchored by Wal-Mart, CostCo and Home Depot, and remains one of the highest grossing power centers in San Diego County.
 
Most of the manufacturing base is located along Woodside Avenue North and Prospect Avenue. The Wheatlands Industrial Park along state Route 67 is home to Alt's Tool and Machine in their new 90,000-square-foot headquarters, and Scantibodies Laboratories, which employs 350 and is the sixth largest biotech employer in San Diego County.
 
Santee's success is partly due to its easy access to freeways and transportation. At the crossroads of state Route-52 and state Route-125, Santee sits just 20-25 minutes from downtown San Diego, Sorrento Valley, and South Bay. SR-52 links the community to I-15 and points west. SR-125 links the community to Interstate-8 and South County. Construction will start next year on an extension of SR-52 that will connect the freeway to state Route-67, and is projected for completion by 2012. Santee is slated to become a premier business location within the San Diego region.