Istanbul - Cairo is a classic overland route. It is a route that has been traveled for centuries, particularly during the Ottoman empire. Historically it overlapped with the Hajj, with many people covering all or part of the route as part of their pilgrimage to Mecca.
Backpackers discovered it in the '70s and '80s, with hippies searching for spiritual peace who departed to Jerusalem from Istanbul instead of going to India via Iran, Afghanistan and Pakistan. After the peace treaty between Egypt and Israel, onward travel from Jerusalem to Cairo became a possibility. For visa reasons (see below) the route is almost always traveled Istanbul-Cairo, few choose to go the opposite direction. The guide book series Lonely Planet made the route even more popular by publishing their "Istanbul to Cairo on a shoestring".
See also Tips for travel in developing countries; advice there applies to most of this route.
As the area is volatile and subject to sudden political changes, it is essential to listen closely to the news before and during your trip. Read the travel warnings issued by your government carefully and heed them.
One reliable alternative for securing a Syrian visa is to apply at the Syrian Embassy in Istanbul. Processing time was less than 8 hours, so it is possible to apply in the morning and return later in the afternoon to retrieve your passport.
Since Syria is technically still at war with Israel, any proof of a past or future visit to Israel will result in being denied entry to Syria, even with a valid visa. Thus people intending to visit Israel on their trip travel from Turkey to Egypt, not the other way around. It is possible to keep a visit to Israel out of your passport if you enter and leave Israel through the Allenby-King Hussein bridge border crossing and request the Israeli officials to stamp a piece of paper instead of your passport. But this method is not very reliable.
Border crossings: Mardin-Nusaybin-Kam??l? (railroad, currently open), Mardin-Nusaybin-Kam??l? (highway border crossing, currently open), Mardin-?enyurt-Derbesiye (highway border crossing, currently closed), ?anl?urfa-Ceylanp?nar-Ra_fsal Ayn (used during religious festivals), ?anl?urfa-Akcakale-Tell A?abeyyat (highway border crossing, currently open), Gaziantep-Karkam??-Carablus (highway border crossing, currently open), Gaziantep-Cobanbey-Akderun (railroad and highway border crossing, currently closed), Gaziantep-Islahiye-Ekbez (railroad, currently open), Kilis-Oncup?nar-El Selame (Azez) (highway border crossing, currently open), Hatay-Cilvegozu-Bab Al Hawva (highway border crossing, currently open), Hatay-Yaylada??-Kesep (highway border crossing, currently open).
Antakya-Aleppo is the crossing most frequently used by travelers. There are buses across the border.
Aside from the bus, there is also a [http://www.seat61.com/Syria.htm train] that runs into Syria once a week.
Less dangerous but far more annoying are the various touts.