Currently, OnMouse events work perfectly in 2D as long as colliders never overlap, but in isometric games it's very common for sorted/layered sprites to overlap while on the same Z axis. It's at this point the OnMouse events become unusable - since the collider which the mouse click triggers is often visually behind another object - and incorrectly fires the OnMouseEnter/Down/etc. There is a workaround of sorts; Ditch OnMouse completely & fire a RayCastAll and then sort the colliders it hits by the Y position of the transform. The lowest Y position gameobject then does whatever code you tell it to do. Which seems to work - but is far from ideal and can get rather messy in code, since you miss out on the instant benefits of OnMouse or OnPointerDown. Plus it adds a whole bunch of needless processing. So I believe there's a reasonable request here for some kind of new built-in '2DMultipleColliderMouseOver' event method - or possibly even a change to how the renderer/collider shares information between eachother in 2D, so a collider always knows it's 'on top visually', if not physically.