there are a couple different ways to approach this...
say we're in C major. a pure major third is 5/4 or about 386 cents. if you try arriving at the same E by a chain of pure fifths (3/2 or 702 cents) C - G - D - A - E you end up with a 81/64 E, about 408 cents. the discrepancy between these two E's is 81/80 or 21.5 cents, known as the syntonic comma. temperament is the distribution of these commas, either unequally (in meantone) or equally (12-tone equal temperament). now because C is a 'close' or optimized key in meantone you don't run into enharmonic discrepancies. but if you take a chain of 12 meantone fifths
Ab - Eb - Bb - F - C - G - D - A - E - B - F# - C#
an extension in either either direction creates an enharmonic (G# vs. Ab). so in stopping at 12, the C# - Ab interval is a 'wolf fifth,' basically very out of tune. that is why baroque composers (typically speaking) did not write in the 'distant' keys of C# or Ab. there are some instances of baroque harpsichords/organs built with split black keys, but because of the added technical complexity of the instruments it never caught on.
as far as orchestral music goes...DB's are most often playing roots and fifths so tuning adjustment isn't as big an issue...but if you are playing violin or trumpet you become very aware of these discrepancies, and conductors will often talk of 'sweetening' some chord by raising or lowering certain notes from their equally tempered values.