This can be due to a number of many, very different reasons:

1. Wrong/No Activity: the Harmony remote will only send your button presses to Remote Buddy 2 if you've selected the "Remote Buddy 2" activity. Activities on the Harmony remote are - depending on model - chosen either via the remote's touch screen or by pressing one of the buttons from e.g. a "Music, TV, Movie" row at the top of the remote. Please note: short and long presses of these buttons can select different activities.
2. Bluetooth turned off: please make sure that Bluetooth on your Mac is turned on.
3. Harmony Hub not paired: the Harmony Hub sometimes looses the Bluetooth pairing when making changes to its configuration. Use the Harmony Control app on your device and try to control your Mac through it and you'll be asked to pair your Harmony Hub to your Mac if the connection can then not be established.
4. Empty batteries: if you can't control any devices with your Harmony remote at all, while using the "Harmony Control" app on your iOS device still works, chances are the battery of your remote needs to be replaced. Logitech provides instructions for this.

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