Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is a powerful technique for the analysis of organic surfaces and interfaces for many innovative technologies. However, despite recent developments, there are still many issues and challenges hindering the robust, validated use of ToF-SIMS for quantitative measurement. These include: the lack of metrology and fundamental understanding for the use of novel cluster primary ion beams such as C60ⁿ⁺ and Ar₂₀₀₀⁺; the need for validated and robust measurement protocols for difficult samples, such as those with significant micron scale surface topography; the lack of guidance on novel data analysis methods including multivariate analysis which have the potential to simplify many time-consuming and intensive analyses in industry; and the need to establish best practice to improve the accuracy of measurements. This thesis describes research undertaken to address the above challenges. Sample topography and field effects were evaluated experimentally using model conducting and insulating fibres and compared with computer simulations to provide recommendation to diagnose and reduce the effects. Two popular multivariate methods, principal component analysis (PCA) and multivariate curve resolution (MCR), were explored using mixed organic systems consisting of a simple polymer blend and complex hair fibres treated with a multi-component formulation to evaluate different multivariate and data preprocessing methods for the optimal identification, localisation and quantification of the chemical components. Finally, cluster ion beams C60ⁿ⁺ and Ar_500-2500⁺ were evaluated on an inorganic surface and an organic delta layer reference material respectively to elucidate the fundamental metrology of cluster ion sputtering and pave the way for their use in organic depth profiling. These studies provide the essential metrological foundation to address frontier issues in surface and nanoanalysis and extend the measurement capabilities of ToF-SIMS.