open(my $fh, '/my/huge/file') || die $!;
binmode $fh;

my $separator = "\r*\n|\t|whatever";
my $buffer = '';
my $block;
while (sysread($fh, $block, 4096)) {
  $buffer .= $block;
  while ($buffer =~ /$separator/) {
    process_line($`.$&); # prematch + match
    $buffer = $'; # postmatch
  }
}
print "--\n";
process_line($buffer) if $buffer; # remainder, if any.

close $fh;
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This gives you full control over how to split the data into lines, without significant memory overhead.