Headed out from Earth within the Solar System, Sol and Earth both may be used as reference.
When traveling in interstellar space with stellar systems themselves traveling at varying velocities even within the Local Cloud; it probably gets even more discombobulating at the scale of the Bubble ... and beyond - How would one navigate?
Say, we developed interstellar travel and were able to send a probe on a round-trip to a neighbouring system. The probe wouldn't be able to rely upon a history of it's outward trip because the systems would have moved a little during the journey. The same would probably apply to a beacon because of the lag involved. What could one use as a navigation reference? Is there an interstellar map with system velocities and stuff maintained somewhere?