The continuing success of the combinatorial approach is heavily reliant on analytical methodologies, which allow for the rapid and accurate characterisation of medicinally relevant molecules from compound libraries. Mass spectrometry has recently been touted as the most suitable tool for a range of combinatorial applications such as structural elucidation and screening. The refinement of conventional methods, developments of techniques such as Fourier transform ion cyclotron resonance and new screening methodologies have allowed the medicinal chemist to tackle the growing analytical challenges posed by combinatorial chemistry.