When strokes seem to do nothing, check these in order:
A selection is active elsewhere. Tools only affect pixels inside the current selection—and Show/Hide Selection Control+Command+H may be hiding its outline. Press Escape or choose Selection > Select None Command+D.
The pixels are a protected colour. Protected palette colours (P badge) act as a mask and can’t be drawn over. Command-click the chip to unprotect.
You’re on a different layer. Drawing lands on the selected layer, which may be hidden or behind an opaque layer. Check the inspector.
The Pencil is erasing. The Pencil removes pixels that already match its colour—use the Pen P if you want to always paint.
Single-key shortcuts (tools, X, Z…) are suspended while a text field has focus—for example just after renaming a layer or palette. Click the canvas first.
While a sheet or dialog is open, most menu commands are intentionally disabled until it’s dismissed.
The document has a non-square pixel aspect ratio—either from a system preset (Famicom, Atari ST, Mega Drive…) or an -aspect import. This is a display setting only; exports use square pixels. Choose Canvas > Pixel Aspect Ratio Option+Command+R and set it to 1:1 if unwanted.
Colours still in use on any layer can’t be removed from the palette. Replace them first—the Fill tool with Control held (non-contiguous) recolours every matching pixel on a layer in one click.
See the support page for ways to get in touch.