When it exceeds the xls boundary of 65k by a bit, you're slightly vexed, but have little trouble to split or convert.
When the quantity of formulas causes loading to last longer than a minute, you know it's high time to grab yourself a nice cuppa tea.
When you accidentally press delete column and the screen freezes, you either ragequit and vow off excel programming language, or you ragequit and start over whilst saving every step of the way.
You shouldn't be handling masses of data sources in excel. You get a program (eg db) to handle the data, and export a SUBSET of the results for flexible manipulation (by someone else) at most. Pretty handy as a rudimentary calculator and search tool in a pinch. Otherwise, you're doing it wrong.