Might not be the most obvious example, but losing to Middlesbrough on that Friday night in April 98 was definitely a defining game for me. It was the first time I actually realised we were doomed and going down to the 3rd division. Before that I just assumed we'd get out of it, but from memory Gazza was just taking the piss out of us and we were absolutely woeful, no spirit, no desire, and even less quality!
On a more positive note, Newcastle away in 2012 was a monumental game for us, as was the Everton away game in 2014. Both of those wins felt like title winning games. Obviously there were a few more bends in the road in 2012, but the Newcastle game definitely felt like a huge turning point.
Also would have to include the ECWC game against Zornic Gabrese, bit before my time, but I'm sure some older blues will be able to offer other European games from that season?
Also didn't we beat AC Milan in the UEFA Cup once? That must have been a pretty big deal at the time?