The clinical significance of phosphodiesterase 5 (PDE5) inhibition is increasingly understood following the pioneering work with sildenafil, and the continuing development programmes for both sildenafil and other marketed inhibitors. Since the initial launch of sildenafil for male erectile dysfunction (MED), approval has now been granted for treatment of pulmonary hypertension, whilst ongoing studies have indicated the potential of PDE5 inhibition for the treatment of a range of additional indications including cardioprotection, memory retention and diabetes. Many of these additional indications are best suited to chronic oral dosing and emphasise the need for highly selective inhibitors with extended duration of action. This article will focus on a research programme aimed at the discovery of improved second-generation PDE5 inhibitors. Essential features of these new PDE5 inhibitors would be enhanced selectivity across the whole PDE family and pharmacokinetics compatible with once daily dosing. Key elements used in this programme are high throughput screening (HTS), exploitation of co-crystal structural information for bound inhibitor in the PDE5 active site, and employment of parallel chemistry to speed progress. Under the guidance of co-crystal structural information, a non-selective HTS hit with poor physicochemistry was initially modified using parallel chemistry to give a lead compound (3) that established a new PDE5 inhibitor series. Notably, (3) displayed physicochemistry compatible with a long plasma half-life, and wide chemical scope. Subsequent optimisation of (3) using crystal structure information to guide design, led rapidly to highly potent and selective PDE5 inhibitors (47, 50). Continued focus on physical properties through ligand efficiency evaluation and lipophilicity (cLogP), maintained the inherently desirable physicochemistry of the initial lead.