Can allergy medicine (i.e. zyrtec) become ineffective after a while?

Tolerance develops: A tolerance to zyrtec may have developed. Switching to Allegra or Claritin (loratadine) for a while may help. Once those stop working going back to zyrtec may work.

Yes: Yes, Zyrtec (cetirizine) can become ineffective after a while. Zyrtec (cetirizine) tends to block histamine responses; however, the immune system diversifies with time and sends additional signals to respond to allergy (develops an adaptive response with IgE antibodies, B cells, T cells, etc). Once this occurs, antihistamines only block a subset of the allergic immune response.