Good question. If you can spread your processing in smaller bits and you can get the smaller bits called from the MainLoop, everything will work. The way I do it in one application is that I build my own MainLoop:

use Tk::Event qw(DONT_WAIT);

while (1) {
  if ($self->run) {          # test if we need to process 
     $self->process_a_bit()  # process a tiny bit
  }
  return if $self->quit;     # test if quit status was set
  DoOneEvent(DONT_WAIT);     # do normal Tk event 
  select undef,undef,undef,0.0001; # wait for a bit
}
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I did this, because my processing was not easily adjusted into the normal Tk::Eventloop processing and it needed to be called a lot ("live" 44Kz audio stream processing, with 100 samples per process_a_bit call)

If you want to go this route, you want to adjust the timing of the select() and process_a_bit() calls until your GUI and processing run fast enough, and it doesn't lock up the whole machine when there is no processing being done :-)

Alternatively, if you're able to run your processing based on file events or signals, you can take a look at the Tk::Eventloop documentation for registering extra events in the normal MainLoop.

Oh yes, and you want something like Tk::ProgressBar but you probably know that already :-)