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The significant sites I studied in my ancient art history class in college sprung to life on a grand scale on my recent vacation to Istanbul. I was drawn to visit so I could see the impressive structures I had studied, as well as experience the evolution of Turkish culture firsthand. The Hagia Sophia, one of the most popular tourist spots for good reason, was incredible -- so impressive that such a massive structure was built more than 1,500 years ago.
For tourists new to the city, I would recommend staying in the Sultanahmet area, the most historic (albeit touristy) part of town. Most of the hotels in this neighborhood are small and not major brands. (Places like the Swissotel and Grand Hyatt aren’t in this part of town -- though you will find a Four Seasons.) Here you're surrounded by the most well-known sites, including the Hagia Sophia, Blue Mosque, Topkapi Palace and Basilica Cistern. You can walk to them within minutes -- and then head back to your hotel for a mid-afternoon nap if jet lag strikes.
I was surprised by just how clean and modern the city of Istanbul was. I expected it to more closely resemble Cairo than Western European cities, but it felt very western. I thought the Sultanahmet area was cleaner than San Francisco! That said, Istanbul is a predominantly Muslim city, so it's best to dress in a way that is respectful of the Muslim culture. This will also allow you to make spontaneous visits to mosques across the city, as women must cover both their knees and hair before entering. (One tip: While the five-times-daily call to prayer transmitted from every mosque is all part of the experience, you may want to check into a hotel with double-paned windows, or there will be no sleeping past dawn.)
Somewhat more off-the-beaten-path highlights included visiting the Church of Holy Savior in Chora -- a Byzantine church decorated inside with beautiful frescos and gold mosaics. I then wandered back to the Sultanahmet area through neighborhoods, stopping by a number of mosques and another Byzantine church along my route.